TITLE Safety and Efficacy of Over-The-Counter Drug Use by the Elderly

" DOCUMENT RESUME

ED 245 148 CG 017 518 TITLE Safety and Efficacy of Over-the-Counter Drug Use by the Elderly. Hearing before the Subcommittee on Health and Long-Term Care of the Select Committee on Aging. House of Representatives, Ninety-Eighth Congress, First Session. INSTITUTION Congress of the U.S., Washington, D.C. House Select Committee on Aging. REPORT NO House-Comm-Pub-98-409 PUB DATE 21 Jul 83 NOTE 507p.; Some pages are marginally legible due to small print. PUB TYPE Legal/Legislative/Regulatory Materials (090)

EDRS PRICE MF02 Plus Postage. PC Not Available from EDRS. DESCRIPTORS *Consumer Protection; Dietetics; Drug Legislation; *Drug Use; Gerontology; Hearings; *Older Adults; Physical Health; *Safety IDENTIFIERS Congress 98th; Long Term Care; *Nonprescription Drugs; *PPA

ABSTRACT This document contains the prepared statements and panel testimony from the Congressional hearing on over-the-counter (OTC) drug use by the elderly. Opening statements are given by Representatives Claude Pepper (chairman), Ralph Regula, Mary Rose Oakar, Michael Bilirakis, Tom Lantos, and Hal Daub. Topics which are covered include the incidence and quantity of drug use by the elderly, health risks, adverse reactions, phenylpropanolamine (PPA), consumer protection, and the Federal Drug Administration's (FDA) role in the OTC drug safety and reguIatiem. Testimony of the first panel on OTC drugs, particularly weight reduction medications containing PPA, is given by representatives of the Health Research Group, the National Broadcasting Company, and consumers. Testimony of the second panel on mail fraud schemes perpetrated against senior citizens is given by consumer advocates representing the United States Postal Service, Criminal Investigations and Consumer Protection Divisions, and the Center for Science in the Public Interest. Testimony of the third panel on evaluating the safety and efficacy of various drugs including PPA is given by medical experts from Georgetown, Indiana, Johns Hopkins, and George Washington Universities. Testimony of the fourth and final panel on the safety and efficacy of PPA is given by industry officials from the Thompson Medical Company, Inc., representing the fields of pharmacy, cardiology, sociology, psychology, and medicine. The three appendices contain additional material on medication use/abuse among the Pinellas County, Florida elderly, the FDA list of adverse drug reactions to PPA, the Washington State Board of Pharmacy review of OTC drugs, and prepared statements of panel representatives (BL)

*********************************************************************** * Reproductions supplied by EDRS are the best that can be made * * from the original document. * *********************************************************************** SAFETY AND EFFICACY OF OVER-THE-COUNTER co DRUG USE BY THE ELDERLY

4" (NJ HEARING BEFORE THE SUBCOMMITTEE ON HEALTH AND LONG-TERM CARE OF THE SELECT COMMITTEE ON AGING HOUSE OF REPRESENTATIVES NINETY-EIGHTH CONGRESS

FIRST SESSION

JULY 21, 1983

Printed for the use of the Select Committee on Aging

Comm. Pub. No 98-409

_U,$DEPA_STMENT OF EDUCATION NATIONAL INSTITUTE_Of EDUCATION EDUCATIONAL_RESOURCES INFORMATION CENTER (ERIC) 7t, This document has been reproduced as received ;ram the person or organization originating it. Minor changes have been made to improve reproduction quality.

Points of view or opinions stated in this doou: ment do not necessarily represent official NIE position or policy.

U.S. GOVERNMENT PRINTING OFFICE

21-436 0 WASHINGTON : 1983 SELECT COMMITTEE ON AGING EDWARD R. ROYBAL, California,Chairman CLWIDE PEPPER, Flo, ,da MATTHEW J. RINALDO, New Jersey, If ACO BIAGGI, New York Ranking Minority lifern&er it ANDREWS, North Carolina JOHN PAUL HAMMERSCHMIDT, Arkansas .rstiNKER, Washington RALPH REGULA, Ohio 'T,I(')".'iAS J. DOWNEY, New York NORMAN D. SHUMWAY, California IA T. FLOR40, New Jersey OLYMPIA J. SNOWE, Maine TY.' )LL! E. FORD; Tennessee JAMES M. JEFFORDSVermont WILLiAM_J. HUGHES; New Jersey THOMAS J, TAUKE, Iowa MARILYN_ LLOYD ; Tennessee _ JUDD GREGG; New Hampshire srio; K . _LIINDINE_New York GEORGE C. WORTLEY, New York MARY ROSE OAKAR, Ohio HAL_DAUB,_Nebiliskti THOVA3 A. LUKEN, Ohio LARRY E. CRAIG, Idaho C'',..ALLYNP A. FERRARO, New York COOPER EVANS, Iowa nyv Et11, B. BYRON, Maryland JIM COURTER, New Jersey WILLI.? 1IR RATCHFORD, Connecticut LYLE WILLIAMS, Ohio DAN 1v1 A 'Florida C_ LAUDINE SCHNEIDER, Rhode Island HENTh A WAXMAN; California THOMAS J. RIDGE) Pennsylvania . "MAE Olerthorria JOHN McCAIN, Arizona KLITI L'R_1)L2KICK_:outh Carolina MICHAEL _BILIRAKIS, Florida BRUI.;F.-VEN-T0,-Miiinesota GEORGE WGEKAS, Pennsylvania BARNEY FRANK, Maana.r4-isetts MARK-D.-SILJANDER,_Michigan TOM LANTOS, Californin CHRISTOPHER H. SMITH, New Jersey RON WYDEN, Oregon MICHAEL DEWINE, Ohio DONA. Li JOSEPH ALB(Y7TA. Michigan GEC 'v. CROCAZETT, JR., MInhig_an WILLI d "ILL BONER; Tennessee IKE_S4IEr.:TON, Missouri DENN S_ N!, IICRT_EL, _Michigan ROBERT A BORSKL_Pennaylvaatia FREDERrii C. (RICK! BOUCHER, Virginia BEN ERDRE7CH, Alabama BUDDY MAr.KAY, Florida HARRY M. PEW., Nevada NORMAN SISISKY, Virginia TOM VANDERGRIFF, Tzxas ROBERT E-WISE _JR., West virgin:a BILL RICHARWON. N- Mr0 JOPC1' LAMBRINOS,Staff Director PAUL SCHLEGEIMinority Staff Director

SUBCOMMITTEE ON HEALT:i AND LONG-TERM CARE CLAUDE PEPPER. Florida,Chairman IKE ANDREWS, North Carolina RALPH REGULA, Ohio, JAMES J. FLORIO, New Jersey Ranking Minority Member HAROLD E. FORD, Tennessee THOMAS J. TAUKE, Iowa MARILYN LLOYD-Tennessee GEORGE C. WORTLEY, New York MARY ROSE OAKAR; Ohio HAL DAUB; Nebraska THOMAS A; LUKEN; Ohio LARRY E. CRAIG, Idaho WILLIAN_R;_RATCHFORD,_Connecticut JIM COURTER; New Jersey BUTLER DERRICK; Sbuth Carolina THOMAS J, RIDGE; Pennsylvania RON WYDEN, Oregon JOHN MUCAIN,_ Arizona_ GERALDINE A. FERRARO, New York MICHAEL BILIRAKIS, Florida HENRY A. WAXMAN, California MICHAEL DEWINE, Ohio BRUCE F. VENTO, Minnesota MATTHEW J. RINALDO, New Jersey IKE SKELTON, Missouri (Ex Officio) DENNIS M. HERTEL, Michigan ROBERT A. BORSKI; Pennsylvania EDWARD R, ROYBAL; California (Eic Officio) BILL HALAMANDARIS,Staff Director KATHLEEN GARDNER CFtAVEDI,Assistant Staff Director JAMES P. OBERLE; Ph. D.;Minority Staff Director CONTENTS

MEMBERS' OPENING STATEMENT Page Chairman Cla,.'',.'pler 1 Ralph Regula . 5 Mary Rose Oak, , ... 7 Michael Husk's 27 Tom Lantos 28 Hal Daub 30

CHRONOLOGICAL LIST OF WITNESSES Panel 1.Over-the-counter consumers and consumer representatives: Sidney Wolfe; M.D., director; Health Research Group; and president; Public Citizen 31 Anthea Sachs, Westport, Conn 38 Gloria Jean Davis, Albany, Ga. 38 Janey Phipps, R.N., Gray, Ky 39 Kathleen O'Reilley, consumer expert, National Broadcasting Co 41 Frank Adam°. Johnson Creek, Wis 45 Panel 2.Consumer advocates: Charles P. Nelson; Assistant Chief Postal Inspector, Criminal Investiga- tions Division; U.S. Postal Service, Washington, D,C. accompanied by George Davis, Assistant General Counsel, Consumer Protection Divi- sion of the Law Department, U.S. Postal Service 71 Bambi-Batts Young, Center for Science in the Public Interest, Washing- ton, D.0 76 Panel 3.Medical experts: Dr. Sorell Schwartz, professor of pharmacology, Georgetown University School of Medicine, Washington, D.0 85 Dr. Shirley Mueller, director of neurology, Reganstreif Health Center, Indiana University School-of _Medicine, Indianapolis, Ind 88 Dr. Thaddeus Prout, associate professor of medicine, Johns _Hopkins Uni- versity School of Medicine; and chief of medicine; Greater Baltimore Medical Center, Baltimore, Md 96 Dr. James Ramey, associate clinical professor at George Washington Uni- versity r.r. 101 Panel 4. Industry officials, Thompson Medical Co., Irm: Dr. Harold I. Silverman, prof&sor of pharmacy, Massachusetts college of Pharmacy and Allied Health Services 114 Dr. Matthew H. Bradley, cardiologist, Miami Heart Institute, Miami, Fla 116 Dr. Charles Winick, professor of sociology,_City University of New York 119 Dr, Rudolf E. Nobel; 'director, Cathedral Hill Obesity Clinic, San Francis- co, Calif 126 Dr. Anthony Conte, beriatrician; Beaver, Pa ...... -- ...... ------129 Dr. Marianne Sebok; physician, affiliated with J. F. Kennedy Memorial Hospital, Frankford Hospital, and Albert Einstein Memorial Center; Philadelphia, Pa 139 Dr.- Frank Funderburk, the Behavioral Pharmaceutical Research Unit of the Johns Hopkins University School of Medicine.. . 147 Dr. Edgar E. Coons, Ph. D., professor of psychology, New York University 196 James Schreiber, Jr 220 James Schreiber, Sr 220 Barbara Ritz 221 Bill Iv

APPENDIX Appendix 1."Medication Use/Abuse Among the Pinellas County Elderly,7 by Operation PAit, Inc. Elder/Ed program, Pinellas Park; Fla.,submitted Page for the record by Representative Michael Bilirakis 223 Appendix 2.Material submitted for the record by Representative MaryRose Oakar: Food and Drug Administration computer printnut listing 1,040 reported adverse drug reactions to products containing PPA 259 Background material dealing with -the Washington State Board of Phar- macy review of over-the-counter drug preparations 317 Appendix 3.Additional material received for the recorit Food and Mug Administration, Public Health vice; Department of Health and Human Services, prepared statement.. 351 Medical Society of the State of New York, Edward Siegel, M.D.,executive vice-preeident, letter 366 The Propprietary Association, Washington, D.C., Allan R. Reicinger, director of legislative relations, prepared statement 367 Thompson Medical -Co., Inc New York, N.Y., Edward L. Steinberg;M Se., 0.D., vice chairman of the board, prepared statement 435

5 SAFETY AND EFFICACY OF OVER=THE= COUNTER DRUG USE BY THE ELDERLY

THURSDAY; JULY 21, 1983

HOUSE OF REPRESENTATIVES, SELECT COMMITTEE ON AGING, SUBCOMMITTEE ON HEALTH AND LONG-TERM CARE; Washington, D.C. The subcommittee met, pursuant to- notice, at 9 a.m., in room 2247; Rayburn House Office Building, Hon. Claude Pepper(chairman of the subcommittee) presiding. Members present: Representatives Pepper of Florida, °akarof Ohio; Ferraro of New York, Lantos of California,Regula of New Jersey, Wortley of New York, Daub of Nebraska; andBilirakis of Florida. Staff present: Bill HalamandariS, Staff director; KathleenG. era- vedi, assistant_ staff director; Kitty Edwards; staff assistant;Bonnie Hogue, intern; Peter Reineck, intern; Andi Samuels, intern;James Ober le, Ph. D., minority staff director; and SusanRoland, minority Staff assistant, of the Subcommittee on Rea lth andLong-Term Care; Mildred Vinicor, special assistant; Bruce Fried, press secretary; Nancy Lea Mond, administrative assistant;and Don Rosen- blum, intern, of Representative Oakar's staff. OPENING STATEMENT OF CHAIRMAN CLAUDE PEPPER Mr. PEPPER. The committee Will come to order, please. I alb pleaged to see my colleagues here thismorning and so many of you in the audienceinterested in A _subject -which we regard as very critical, riaruely, the use of over-the-counterdrugs. You remember recently we discussed the question ofpreicription drugs and the hazards and injuries sustained by theelderly people of thiS country frOm the use of prescription drugs;Now those, of course, are prescribed by registered;qualified docteit. Now, we are today dealing With drugs that are sold in_thedrug- store§ and in public markets-._ I want to commend oneof our vets, distinguished members, Ms. Mary RoSé Oakar. Sheinitiated the suggestion that we have a hearing upon this subject: So, we are very pleased -to be considering this matter. Several weeks ago, as I said, We joined the SenateSpecial Com- tiiittee Aging ih examining drug misuse among theelderlY. You know, people over 65 constitute about 11 percentOf the population of the country. And yet they consume about athird of the drugs that are prescribed. We know that; on theaverage, each elderly person consumes or takes about13 prescription drugs a year. (1) 6 2 Now then, we've discovered about the extent to which the elderly people buy these over-the-counter drugs. So, not only do about 11 percent of the Nation's population consume abouta third of the prescription drugs, but by the year 2000our elderly number will be about 33 million persons and we willconsume about 50 percent of ell the prescription drugs annually. It's rather shocking to think that drugs, whichare supposed to be taken against illness; against disease,may also be a source of illness to elderly people. The estimated national cost of drug-induced 'Aospitalization is close to $21 billiona year. Our joint hearing focused primarily; -as I said,on the problem surrounding_ the use of prescription drugs, and the subject of today's hearing; over-the-counter drugs,or nonprescription drugs, were only incidentally discussed. Yet; nonprescription drugs account for at least 40 percent of all the drugs that are used by elderly people. That is; of all the drugs elderly peopleuse, about 40 pet: cent of them are over-the-counter drugs. They are combined with an average of 13 prescription drugs that the elderly person takes per year. You cansee the amount of drugs that are being consumed by the elderly people of the country alone. Our subcommittee has discovered that Americans spend about $10 billion each year on more than 300;000 over-the-counter drugs available in the United States. And we find, we regret tosay, from $3 billion to- $4 billion of that amount is wastedon products with ingredients lacking evidence of safety or efficacy according to evidence that our subcommittee has received. In other words, it'sa waste of that amount of money paid by the elderly. This is particularly disturbing in light of the fact that elderly people commonly purchase over-the-counter drugs. In fact, about 70 percent, in our figures, of the elderly people buy these over-the- counter drugs. In the last Congress we asked the Postmaster General to under- take a massive investigation of drugs thatare bought by the elderly people through the mail. Man early datewe expect the publication of that report by the Postal Service; which will revealsome Very, very interestingindeed, some shockinginformation. We find that one of the ingredients commonly or often found in the-se drugs that the elderly take is the substance called PPA. That drug is contained in a great many different things that the elderlypur- chase. For example, they are contained in St Joseph's cold_ tablets; Contac capsules, Ayds Weight Suppressant, Alka-Seltzer Plus cold medicine, and diet products Dexatrim; Diadex, Ordinex,among many others. Now, this PPA is one of the popular ingredients in most drugs; at least a great many of them. It has come to be about the fourth most numerous ingredient used in the drugs including prescription drugs. These are the symptoms that generally are associated with the use of these. PPA or in drugs where PPA is an ingredient in it These symptoms include insomnia, nervousness, seizures, severe headaches, and psychosis; as well as elevated cardiac enzymes, hypertension, and cerebral hemorrhage, and in some cases death. The risk associated with the use of over-the-counter drugs in Weight reduction products containing PPA are particularly acute. According to the Food and Drug AdminiStration, three-fourthsof the emergency room visits related to PPA use between1978 and 1981 involved over-the-counter products. The National Clearinghouse for Poison Control Centers quantified these 3 actions reporting 10,000 PPA poisonings last year,at least 1,000 of which resulted in emergency room treatment.In spite of numerous scientific studies and medical evidencewhich documents that PPA causes elevation in blood pressure, the FDA, the agency with responsibility for reviewing theover-the-counter drugS for safety and effectiveness, has taken little action except to conclude that further study is necessary. I was on the "Today Show" this morning and one of the question§ asked was the people that put these drugs out say "Butthe warnings, the warnings are on the labels, don't use except according to directionS." Well, I said, it's just about the same as an- insur- ance policy. People just dodt read thefine print. Ms. O'Reilley here was on the program with me this morning and she will be testifying later on this matter. But we all know that the elderly people, a lot of times,forget about_ their prescriptions, they forget about what the directions are even for their prescribed drugs.They get mixed up on it. A man called me in Miami not long ago, frantically and said"My doctor is out of town and I don't know how to take mymedicine:" Well; he didn't know how to read his prescriptions that are onthe drug§ that had been prescribed by the doctor, let alone readall that fine print on these labels on _a lot of these things. So, it seems to me that the FDA ought to not just rely onpeople protecting themselves. We know how we generallybuy these over- the-counter drugs, We hear somebody say that it's a goodthing to take or we've heard of somebody else taking itwith Satisfaction and we say, "Well, I believe I'll- try," and wedon't read all these little fine print warnings that are on there. It seems to methe FDA should protect the public against anything that ispotentially harmful to them. Well, in the meantime_the 4 million Americans whoregularly buy products containing PPA remain at risk.Obviously for older Americans who _already take numerousmedications and suffer from hypertension or other heart problems,-their risk is much greeter. You see, the warning may be onthere, that little fine print, and it may say if you've got heartproblems don't take this, but they don't read that They just take it, It saysit's for weight reduction or this, that, or the other, and they go right onand take it. The Postal Service will tell us how the dietdrugs they purchased can be obtained by anyone,either over the counter or through the mails, without regard to the health status ofthe_ purchaser. Medi- cal opinions obtained on these diet drugsrevealed they do little to control weight and are especially dangerousif taken by senior citizens: One of the things -that most people don't realizeis that, since, as I said, the elderly people have about 13prescription drugs on an annual basia that they take, now then, when you goadd that they take---z-that _40 _percent of all the drugs they take areover-the- counter, they don't anticipate the sometimeshurtful, harmful; in-

8 4 terraction among these drugs. And you can't read anything about that on the label, and so people just ought not take dangerous drugs, or be allowed access to them, it seems to me. It may be very dangerous to them. So today we will hear from those who purchase these drugs and suffer adverse drug reactions. We will hear from a number of well- known consumer advocates who will reveal the findings of their own investigations of over-the-counter drugs. We will hear from medical experts who will tell us what risks are involved in the use of- over- - the- counter drugs. We will hear from the Food and Drug Administration who will respond to our concerns regarding their reports to monitor adverse reactions to over-the-counter medications. And we will hear from industry representatives who will detail for us their views on these important issues. So; we look forward to hearing these important witnesses this morning on this very important subject. [The prepared statement of Chairman Pepper follows:]

PREPARED STATEMENT OF CHAIRMAN CLAUDE PEPPER Ladies and gentlemen. Members of the subcommittee. Today we are convening a hearing to examine the safety and efficacy of over- the - counter drug usage among the elderly. My distinguished colleague from Ohio, Congresswoman Mary Rose Oakar, requested this hearing by-the subcommitteeand, I was honored to grant that request and to comment briefly on this important national issue. Several weeks ago, we joined the Senate Special Committee on Aging in examin- ingdrug,misuse among the elderly. We found that the problem of drug misuse among older Americans is particularly alarming in light of certain demographic trends: Today, older Americans represent 11 percent of the Nation's population, yet theY consume about one-third of the 1.5 billion prescriptions written annually; on the average, elderly take 13 prescriptions a year; By the year 2000, our elderly will number about 33 million persons, and consume about 50 percent of all prescription drugs annually; Elderly are twice as likely to be seen in hospital ertie:gency rooms as those under age 60; and; when reactions occur the hospital stay is doubled; The estimated national cost of drug-induced hospitalization is close to $21 billion annually; Our joint hearing focused primarily on the problems surrounding the use of prescription drugsand the subject of today's hearing "Over-the-Counter (OTC) Drugs; or Non-Prescription Drugs" were only incidentally discussed. Yet, nonprescription drugs account for at least 90 percent of all drugs used by the elderly; and when they are combined with the 13 prescription drugs an average senior consumes annually theside effects and adversereactions become even more unpredictable. My subcommittee has discovered that Americans spend about $10 billion each year on the more than 300,000 OTC medications available in the United States today. As much as to $4 billion are wasted on products with ingredients lacking evidence of safety or efficacy; according to evidence reviewed by the subcommittee. This is particularly disturbing in light of the fact that elderly commonly purchase OTC drugsalmost 70 percent of the elderly use such medications, as compared with 10 percent of the general adult population, Last Congress, I asked the U.S. Postma "er General to join my committee in undertaking a massive investigation into frauds perpetrated through the U.S. mails. One fact of that investigation attempted to determine what senior citilensget when they purchase drugs through the mail. The Postal Service will release a portion of our Findings in that investigationspecifically -as they relate to non-prescription diet drugs which contain a substance called 'WA." Consider the following facts regarding PPA: According to the FDA, over 700 prescription products contain PPA; It is ranked sixth among the toe ten generic substances contained in all drugs when OTC medications containing PPA are addedit becomes the fourth most commonly used generic substance in all drugs; ii

Nearly -million Americans consumed-10 billion doses of products containing PPA last year. Every household medicine cabinet probably includes one product containing PPA: Among the hundreds of OTC products containing PPA are: St. Joseph's cold tablets Contac capsules. Ayds weight suppressant; Alka Seltzer Plus cold medicine; and diet_ products Dexat rl Diudex; Ord i am_ong_ n umerous. others; The following advt, le reactions associated with PPA, according to FDA files, include: insoninia, nervousness, seizures, severe headaches, and psychosis,- as well as elevated cardiac enzymes, hypertension and cerebral hemorrage and death; The risks associated with the use of-OTC and weightreduction products containing IPA are particularly acute. According to the FDA three-fourths-of the emergency room visits related to PPA use between 1978 and 1981 involved OTC products; The National Clearinghouse for Poison Control Centers quantified these reactions, reporting _10;000 PPA poisonings last yearat least 1;000 resulted in emergency room treatment. In _spite of numerous scientific- studies and medical_ evidence which_ documents that PPA causes -an elevation inblood- pressure, the FDAthe agency with responsibility for reviewing OTC-drugs for safety and effectivenesshas taken little action except to conclude that further studies are necessary. In the meantime, the 4 million Americans who regularly buy products containing PPA remain at risk. Obvi- ously, for older Americans who already take numerous medications and suffer from hypertension and other heart problemstheir risk is much greater.

_ The Postal_ Service will tell us how_the.diet _drugs they-purchased can be obtained by anyone_ either over - the counter or through the mails_without regard to the health status-of the purchaser. _Medical opinions obtained on these diet drugs revealed they do-little to control weight and are especially dangerous if taken by senior- citizens. Toiday, we will hear from those who purchased-these drugs and suffered adverse drug reactions; we will hear from a number of well known consumer advocates -who will reveal the findings of their own investigations of OTC drugs; we will hear from medical experts who will tell us what risks are involved in the use of OTC drugs; we willhear _from th_e_Food_and__Drug_Adrninistrationwho will respond to our concerns regarding their efforts. to monitor adverse reactions to OTC medications; and we will hear from industry representatives who will detail for us their views on this important issue._ 1 look-forward to hear the testimony and learning-what the Congress might do to help curb the incidence of drug misuse among older Americans. Thank you. Mr: PEPPER: Mr: Regula? STATEMENT OF REPRESENTATIVE RALPH REGULA Mr. REGULA. Thank you, Mr. Chairman. First of all, I want to compliment you on having this hearing:1 think it's very important. that we examine this topic Ponce de Leon looked for the magic fountain and I think there's always a temptation in the modern world; with the tremendous advertising budgets; that people look for the magic drug or the magic pill that somehow will cure all ills, and, therefore, it's important that we examine this problem as it impacts on the elderly. I would like unanimous consent to make my statement a part of the _record: Mr. PEPPER. Without objection, it will be so ordered. [The prepared statement of Representative Regula follows:]

PREPARED STATEMENT OF REPRESENTATIVE RALPH S. REGULA Mr. Chairman, I want, to thank you for holding this hearing today. Not long ago our subcommittee joined with the Senate's Special Committee -on Aging tainvesti- gate and discuss the problems people; especially the elderly; face with prescription drugs. At that time I was shocked to discove that the elderly; which comprise approximately 11.4 percent of our population, consume nearly one third of all prescription drugs-in the United States. Additionally, they average, 'n consumption, 13 prescription drugs per year. At the same, Mr, Chairman, we were made vividly aware of the tremendous lack of knowledge in the Area of how one medication interacts 6

with another medication. In relation to our elderly we are talking of not just twoor three drugs which must interact, but an average of 13 different drugs which must interact; To make matters worse, the tests which are conducted to determine the efficacy and safety of these drugs are conducted, in the final stages, withpersons generally male, of good health between the ages of 25 and 35. Now I am nota medical researcher but I think I can safely say that the metabolism of a young male in good health and the metabolism of an individual over the age of 00 or 65. many of which are women. differ greatly. This is why I believe these hearings are vital to the well-being of our senior citizens whose numbers will more than double to neaHy 23 percent of the population by the year 2025. Their health and their lives, Mr. Chairman, dependon the knowledge of drug interaction which we now lack. But this is only one part of the problem we-face. We are here today to investigate the second part of this problem: over-the-counter drugs tOTC). It is difficult to gain an accurate figure of the elderly'suse of over-the- counter drugs because these are not required to be logged in as they are sold. How- ever, it is estimated that the elderly consume approximately the same percentage tone third); if not more, of all OTC sold in the United States as they do of prescription drugs. Unfortunately, we lack the same knowledge needed for OTCas we do for prescription :drugs. Add this 31 percent of all OTC with the average of 13 prescription drugs the -elderly consume per year with the lack of knowledge we have on drug interaction: the lack of tests and studies as to how even one drug affects the metabolism of theover age fia group as opposed to the young healthy males; the fact that many times the patient is not fully aware of how or when to take their medication; what not to mix with other medications; and the fact that many- patients are too intimidated to insist that their physician sit down with them to discuss all the ins and outs of their illness and the medications given to cure that illness, andwe now have a definite life threatening situation. Something must be done to correct these problems. We must make the public more aware of the dangers of_ mixing medication; both prescription and over-the- counter drugs. Additionally, we must make the medical community aware Of their reponsibility to their patients to inform them of exactly what medications theyare taking; of what over-the-counter drugs the patients should notuse in conjunction with their prescriptions and that above all they should first investigate the patients' medication history to discover what, if any, other medication the patient hasor is taking. As you remember, we were informed at our joint hearing with the Senate; this history is not always done now. Finally, and most importantlywe should make sure that the drugs which a_re being tested include tests to discover the ramifica- tions of the elderly's consumption of those drugs, I hope this hearing will accomplish an increased awareness in the public, medical community, pharmaceutical companies producing these drugs, and the FDA which oversees the governing aspects of the sale of these drugs. Thank you Mr. Chairman. Mr. REGULA; Just a couple of comments; One of the important reasons for a hearing of this type is a recognition of the different ways drugs impact on people, particularly in relationship to age. The elderly metabolize drugs somewhat differently thana younger person and therefore a drug would have a different impact on that individual; Second, as you point out Mr; Chairman; there is the interreac- tion of the prescription with nonprescription drugs and, of course, just the sheer volume of drugs creates a problem if taken in any sizable quantities and at the same time. Third, I think there is a temptation to use nonprescription drugs because of the savings in cost; It's expensive to get a prescription; it involves a visit to a physician usually, or some type of a medical service. The temptation would be, and particularly with the power of advertising; to say that I'll find that magic _drug that- will solve the problems without any great cost. I think having a hearing of this type will certainly focus attention on the problem and make us 7 all more aware of it and perhaps, as a result of ourfindings from this and other hearings, we can make recommendations to the appropriate committees for more effective control: Also; the appropriate agencies will be sensitized to the problem. Mr. PEPPER. Thank you very much, Mr. Regula. Now, as I said, the lady that suggested that we have this hearing on this subject was Mary Rose Oakar. We are pleased tohave her give her opening statement STATEMENT OF REPRESENTATIVE MARY ROSE OAKAR Ms. OAKAR. Thank you, Mr. Chairman. Thank you -for the leadership you have provided on this issue and for the courage you've demonstrated in having this hearing. There has been a tremendous amount of pressure placed on you as Chair and your staff and my staff and others, not to have this hearing. I'm very proud of you; Mr. Chairman, and your concern for the consumer. We are not here to indict-the entire drug industry. We realize that they have made significant contributions to the American public and we want to make that very, very clear. What we are here to say; though, today; at least this member; is that the drug industry for Americans, is a $25 billion industry; and with respect to the elderly population, 20 percent of their expenses for health care go to over-the-counter drugs. And that's the subject of our hearing today. More than 70 percent of the elderly rely on over-the-counter drugs as opposed to 10 percent of a more youthful population. And Specifically, when you're talking about the diet pilloven-the- counter industry; we knowthat this is a huge industry. And we know that people spend about $200 million a year on over-the- counter and pills that they buy in the mail, et cetera. We know that there are 10 million people who are buying these pills; most of whom happen to be women. You know, the advertising is always geared toward women, and some of us feel that it's a certain degree of exploitation. I'm concerned that ;-Mr. Chairman; in the invitations that were sent out the FDA, at leaSt at this moment, did not respond. We did contact Secretary Heckler last night and asked her if she could pos-_, sibly send somebody. They have declined to be here, when some of the issues really relate to them. Also, the proprietary association that was §o concerned about this hearing and harassed my staff so much about this hearing; declined to come today. It is the umbrella organization for the drug industry. And really, I think it's important to have their point of view. Mr. Chairman, one of the problems lies in the fact that with respect to over-the-counter drugs there is no mandated reporting when it comes to adverse reactions to FDA. The FDA was supposed to be looking into over-the-counter drugs: With respect to this drug, specifically; let me just give you this as an example, and there are hundreds of others just like this. PPA was on the market before we passed the Food and Drug Administration Act. As a result it was not monitored and was exempted from any kind of attempts to monitor and scrutinize, since it came out in 1937 before the act was 12 8 passed in 1938, there was no mandated scrutiny. So, PPAwas exempted; Then they required premarket proof for the effectiveness of drugs in 1962. In 1972 the FDA said, "Well,we will review over- the-counter drugs that escaped pre-market safety and effectiverieSS requirements." Finally, in 1975, FDA got around to havingan advisory panel that would look at PPA and other types of miscella, neous drugs, and, finally; an advisory panel did finish its report 4 years later, in 1979, in terms of reviewing PPA. The panel gave that report to the FDA. While they publishedublished some interest= ing observations in the Federal Register; some of whichappear to be contradictory to me, in 1983 they still have not, inany way; shape; or form mandated any kind of requirements with respectto this drug. How did I get interested in thisI got interested in this because my constituents were affected adversely. A young girl experienced psychotic behavior and had psychiatric treatment. Shewas an obese young lady; 18 years old. We were veryaware of her case and very concerned about it. We found out that while she was taking these pills for dietary purposes, her friendswere popping these pills to get a little high; It was kind of a substitute for illegal drugs at a high school level. So, that was a youthful case. Then we got a call froth another individual who was an older American; a woman who was 585ears old, Who indicated, and whose children indicated; that her doctor felt she had gotten a stroke by taking over-the-counter diet drugS. So we decided to pursue this and found out that; indeed, therewere some consumer advocates who had done some excellent studies of this Also; we realized that there were hundreds, if not thbusandS, or millions of people who have experienced tremendous adverse reaction from this type of over-the-counter drug. Furthermore,we realize that PPA has not experienced the scrutiny by FDA that it should have had, that the FDA has dragged its feet with respect to this drug. It's as if they hold up their hands and don't really care about the American public and the reaction to this kind of drug. Mr. Chairman, I have introduced a bill today that, hopefully, will plug up some of the problems with respect to the FDA. If FDA is not going to use its discretionary authority, then we have to force them to use the power. So we have mandated and required that adverse reactions to over-the-counter drugs be reported not only to FDA, but to this Congress. And there are other areas in the bill. With your permission, Mr. Chairman, I would like to submitmy written statement along with a summary of- the_legislation that -I plan to introduce today, "The Safe and Effective Drug Act of 1983." In addition; I would also like -to submit for the hearing record a series of six articles by Judy Grande which appeared in the Cleve- land Plain Dealer last week. This excellent series examined the FDA and its regulation of the drug industry -in great detail. An 8- month investigation by Ms. Grande brought her to the conclusion that the national system that is_ supposed to protect the public from unsafe drugs does not work. Her series examines the relationship between FDA and the pharmaceutical industry, deficiencies in clinical testing procedures; and the role of Congress and the Reagan administration. Anyone with a genuine concern for the

13 9 health and Safety of the American public ought to take the time to read this series. Mr. PEPPER. Without objection, the material will be received. [The material Submitted by Representative Oakar follows:]

PREPARED STATEMENT OF REPRESENTATIVE MARY ROSE OAKAR I want to thank Chairinan Pepper and the Subcommittee on Health and Long- term Care for holding this hearing on the safety and efficacy of over-the-counter drags. Today's hearing is an important followu_p to our joint hearing with the Senate Special Committee on Aging on June 28th In the course of that_hearing, I raised some serious concerns about the performance of the Food and Drug Adminis- tration in protecting the public from unsafe and ineffective drugs: Although the June 28th hearing focussed on prescription drugs, I made it clear then that my concern covered over-the-counter medication as wellI think that as part of the Sub- committee's series of hearings on"the Crisis in_Health Care," it is appropriate that we broaden our focus to include these medicines which represent about 40 percent of the drugs used by the elderly. In the JUne 28th hearing we discussed drug interactions that result when an el- derly_person 's taking multiple medications, sometimes under the supervision of-two or more physicians. The potential for such interactions is multiplied whenOTC drugs_ are utilized by an elder person_ already taking several prescription drugs, We would not expect the average older American or; for that matter; any consumer to know that even such a common OTC drug as aspirin can interact dangerously with many prescription medications. An additional source of concern is the factthat elderly Americans are more susceptible than any segment of the populations to the so-called "hidden disease"high blood_ pressure and diabetes, 70 percent of peoPle With serious high blood pressure are either completely unaware of it or receive inadequate treatment. 45 percent Of the 11 million diabetics in this country are undiag7 nosed. When one considers the easy availability of OTC's -and the lack of consumer awareness about potential interactions, the implications for ourelderly citizens are truly frightening. There are currently about 300,000 OTC drugs available in the United StateS. Retail sales are estimated at $5.2 billion annually, We_are all aware of the wide availability Of these drugs: They are sold everywhere; and not only in the - corner drugstore: the neighborhood supermarket is likely to have just as wide a selection of OTC products as the local pharmacy. Most Americans assume-that drugs they can buy so easily and relatively cheaply must be rather benign. Unfortunately, the average consumer is the victim of a prime example of "circularlogic" "Thej, must be harmless that's why they're over-the-counter!" Both FDA officials and drug manu- frietUters who should know better subscribe to the same dubious_reasoning: they are OTC's because they are harmless; they are harmless because they are OTC's. The truth is that these drugs are largely unregulated, and many OTC products have been on the market for decades without ever being proved safe and effective. They have gone through no pre-marketing approval process, yet they-are available to every segment of the population; often in a setting where noqualified pharmacist is available to give advice, How did this incredible situation_come about? In 1938, the Food Drug and Cosmetic Act provided for the first time_a comprehensive system for regulating the sale of drugs. The Act required a license for all drugs introduced after that date unlesS the drug was "generally recognized as safe." It also empowered the FDA to remove fram the market any-unlicensed drugs introduced after 1938 which were not generally recognized as safe (GRAS). In 1962, Con- gress adopted the Harris-Ketauver Amendments, which requiredthat drugs also be proven effective for their intended uses. The need_for_the 1962Amendments, and thiS is a key pia; was documented by testimony presented at Congressionalhear- ings that the use of safe but ineffective drugs may not only be a waste of consumers' money, but also may be positively injurious to the public'shealth, since the use of any drug entails certain, unknown risks. Both the original FDC Act and the 1962 amendments contain"grandfather" clauses which exempt drugs on the market at the time the statutes were enacted from the GRAS /E requirement. Thus; unless they are generally recognizedby experts as Safe and effective, most; if_ not virtually all; OTC drugscan not_legallybe sold. One way of assuring that OTC drugs meet this criterion would be for them -to go through the new drug application" (NDA)-process.However, very few manufacturers of OTC drugs have taken this route. Therefore, the vast majority ofOTC 10 drugs marketed today are being sold on the basis of their manufacturers' claims that they are GRAS/F. How has the FDA responded_ to this situation? In 1966, the FDA began investigating the extent to which OTC drugs met the new efficacy requirements. The agency appointed the National Academy of Sciences National Research Council to review approximately 420 OTC drugs which were "broadly representative of the whole-range of the OTC market." Reporting in 1969, the NAS-NRC concluded that only 25 percent of those drugs were effective for even one use. Not surprisingly, this finding gave the FDA "cause for concern" about OTC drugs in general. It took until 1972, 10_years after the efficacy amendments were passed; for the FDA- to begin a systematic review of all OTC drugs. At that point; the agency realized that there were -two possible ways it could proceed to bring OTC drugs into compliance with the law. First, it could bring enforcement actions in- federal -court against individual products. This approach, it was estimated, would place an "enormous burden" on the agency, since there are around 300,000 OTC bran& on the market. A second approach would be to proceed by administrative rulemaking, considering the efficacy of particular ingredients found on OTC drugs. This was deemed a more reasonable way af tackling_the task because the _agency estimated that there were only 200 active ingredients used in all OTC product& (The number turned out to be considerably more; thus far, the FDA has reviewed 731 active ingredients): FDA adopted a lengthy and multi-stage procedure involving expert scientific advisory panels, several stages of published monographs, and, ultimately, a final order establishing the conditions under which the ingredients of the OTC drugs studies are GRAS/F. When the FDA began its OTC review in 1972; the agency estimated that the review would-require five _years _to- complete. The time required to complete the review was significant because it was made clear at the time and has been reiterated since that while the review was being carried out, no enforcement actions would be brought against ineffective OTC drugs. This policy is set out in the FDA Compli- ance Policy Guide, and has been repeated -in- speeches given to other government agencies, and in published textb-o-oks. A 1979 letter from the Chief Counsel of FDA to the Proprietary Association laid out the policy in clearly stated terms: The_period during which the OTC Review makes its stately (?) progressloward_a final monograph is the period during which FDA is formulating its position on that issue: During that period FDA generally will not take regulatory action against a particular OTC product whose ingredient(s) are within the OTC Review pending is- suance of a final monograph covering those ingredient(s). -FDA will take enforcement action in cases of danger to the public health or fraud. Even where FDA does not, as a matter of policy, take enforcement action, the burden of good faith compliance with the law remains at all times with the companies marketing OTC products. There are two major problems with this FDA_ policy; first, the agency is in effect asking a major industry to regulate itself; second, the review process has taken much longer than anticipated; Originally projected to last five years; it has dragged on for eleven years now, and the end is nowhere in sight. In July of 1981, the Direc- tor and Deputy Director of the OTC Review agreed that, realistically, -the review would- probably not be completed until the year 2000.-Based on the FDA's past record of meeting milestones and-deadlines in the OTC Review, even that might be too optimistic an estimate. The FDA has consistently underestimated the duration of the OTC Review. At present, the FDA has published only six final monographs plus three final orders which cover single ingredientsa total of nine final documents tut of_a projected total of 85! All this would not necessarily be cause for concern if all over-the-ccunter drugs were really as benign as most Americans assume they are. However; the expert scientific panels appointed by FDA have found that 69 percent of all the OTC ingredient reviewed are not generally recognized as safe and effective According to the monographs published so far, 37 percent lack evidence of effectiveness, 24 percent lack evidence of safety and effectiveness, and 8 percent lack evidenceof safety. While the FDA continues its "stately progress" towards completion of the OTC Review, the American public is spending billion of dollars on products that contain ingredients two-thirds of which are either unsafe or ineffective, or lack evidence of safety and efficau. Today _I wiLl_ be introducing Letslation that will deal with many of the concerns we discussed at the hearing on the_28th, The general purpose_of_this_legislation is_to strengthen the authority of FDA to control the use of all _drugsprescription and OTCwhich present risks to the public. The bill would put OTC's under post-marketing scruitiny for the first time. Specifically, it will require manufacturers of over- 11 the-counter drugs to report adverse drug reactions toFDA; extend FDA's authority to require manulticturers to_do post-marketingsurveillance; and grant_FDA the au-_ thority to restrict drug marketing if adVerse reactionsdevelop after the drug has been approved: In addition, thv bill will_croate aNational Center for Drug Surveil- I inceWithin FDA; mandate an annual report toCongress on adverse reaction data and FDA'S response to itand direct the Commissioner to establish a program to encourai.;e physicians, institutionalhealth care providers and consumers to report adVerse drug reactions to FDA. Finally, thelegislation will FDA subpoena power it may need to obtain important datafrom drug testers: A case in point which illustrates serious defitieficiesin the OTC Revie_w_program is that of phenylpropanolamine_or PPA as an ingredientin weight control products. This ingredient has been of partic_ular interest to mesince Severn! of my constituents itifornied me of their concern withPPA-based diet pills_ I began researching the issue further and discovered a large and growingbody of evidence linking PPA in diet pills with a variety of adversereactions,_In addition_, there seemed to be sub- stkintial _proof of the ineffectiveness of these pillsfor controlling weight. Further research into the matter gave me reason CO believethat 10 million Americans might be using a product with great risks and very fewbenefits. At today 's hearing, I hope to ezamine thecontroversy surrounding PPA, and hopefully arrive at some answers to certain troublingquestions: how has this product remained on the market for 45 yearswithout ever being ShoWiri to be safe and effective? IS the diet pill industry accepting the "burdenof good faith compliance with the 111W" while FDA completes its review?Are the ten million Americans who use diet pills being misled ordoes the product work for them? In an effort to get at the answers to some of these question& wewill be hearing today from_ victims of serious adverse reactions to diet productscontaining -PPA, doctors and scientists With an understanding of the various aspectsof the PPA Controversy, industry rep rest.tiLities, -iitird FDA officials.. I hope thatduring the hearing we can also grapple with some fundamental questions aboutFDA's_role. Why, after eleven years, has FDA fitiled to move beyond the proposedmonograph stage with a product So widely used and of such dubious value? In general;how can FDA _expedite its OTC Review? Should the agency be giving priority in the review towidely used_ and_ potentially hazardous ingredients like PPA? Why is it taking solong; and when will it be finished? I look forward to hearing from all ourwitnesses, and I hope we can begin to resolve some of the questions 1 have raised.

LETS PROTECT OUR CITIZENS FROM UNSAFE AND1NAFFECTIVE Daucs Modern medicine has come a long way_since the1880s. There are over 300,000 over-the:counter medications and 7,000 prescriptiondrugs readily available in the United States. What is frightening, however; isthat as much as $9 billion is wasted on some of these productswith ingredients that are neither safe noreffective. flow is a senior citizen to know what is safe and whatis not? Not only do 70 percent of our elderly use OTC drug& but the averagesenior citizen takes 13 prescriptions a year and it is a known fa_c_t_that theelderly are twice as likely to be treatedirt an emergency room for an adverse drug reactionthan a citizen under 60 years of age, ObviouSly, this is not a problem that extends beyondthe senior citizen population; it affects all age groups. For many years, I have-been concerned aboutthe performance of the FDA in the effectiveness. A 1969 report to FDA_by the NationalAcade- area of drug safety and of my of Sciences and the NationalResearch Council concluded that only 25 percent a representative sample of over-the-counterdrugs were effective for_even one use More recently, panels appointed by FDA haVefound that 69 percent of all_over-the- counter ingredients reviewed are notgenerally recognized as safe and effective In 152 the FDA began a systematic five yearstudy of all over - the - counter drugS. Today -1l -years laterFDA estimates thatthe review will not be completed until the year 2000. Meanwhile, under current law,manufacturers are not even required to report adverse drug reactions tothe Food_ and Drug Administratibn. This legislation will make the Foodand Drug Administration police the public's health. It will mandate that FDA exerciseauthority that, is now discretionary. It will give the agency new powers to requiredrug manufacturers to report adverse reactions, to subpoena information, and torequire full disclosure of all test results, not simply those that support a newdrug application. Specifically; the bill Require manufacturers of over-the-counter drugsto report adverse drag reactions to the FDA. Under the current system,drug manufacturera Of OTC drugs are not 12 obligated to report adverse drug reactionseven if they are life-threateningto the Food and Drug Administration. Given the FDA the authority to require drug manufacturers to conduct post-marketing surveillance of prescription and over-the-counter drugs and report the findings to FDA. The Food and Drug Administration cannot now require a drugmanu- facturer to survey physicians or health care institutions even if FDA suspects that there may be a serious problem. Authorize FDA to restrict the marketing of a drug ;f adverse reactions develop after the drug has been approved. Although FDA has considerable authority to require further information and tests before a prescription drug is approved, once the drug has -been- marketed, FDA has little authority to regulate itsuse. This provision would allow FDA to restrict a drug to practitioners with special trainingor experience in it use or to practitioners for use in certain facilities. Grant to FDA the authority to subpoena records from drug companies. FDA must rely on voluntarism and the goodwill of drug companies to provide the Information it requests. Requires investigators of new drugs to report the test results of all studies to FDA. Establish a program in FDA to encourage physicians, institutional healthcare providers and consumers to report adverse reactions to the Agency. It is vital that FDA mount an effort for voluntary reporting through such mechanismsas a too- free number or public service media announcements to encourage the reporting of adverse reactions. Establish -a National Center for Drug Surveillance within FDA to monitor reports of adverse drug reactions and ensure FDA action. Mandate an annual report to Congress on reported adverse drug reactions and the actions FDA has taken in response.

[From the Plain Dealer, July 10, 1983) FDA FAILS To PROTECT USPART I (By Judy Grande) INDIANAPOL1S.The heart attack that forced Harrison Pittman to retire from computer programming at age 53 was ahard,blow, but not a fatal one. Pittman had plenty of reason to livea wife, five children, a nice homeand he worked hard at recovering. He slimmed down, took long, slow walks and swallowed every pill his cardiologist prescribed. But an- irregular heart beat remained a year after the attack, and he was sent to a clinic that was experimenting with a new cardiac drug. Pittman signed a form in the clinic consenting to take the drug. Three days later he dieda human guinea pig, U.S. Food and Drug Administration (FDA) records later revealed that Pittman; identified in clinic files only by patient number and initials "HP," received extreme, ly high dosages. He was warned that test with a similar drug killed humans and laboratory animals. His is but one of many stories of human experimentation conducted by an industry so cloaked in secrecy and so skilled at self-promotion that it defies most attempts to regulate it. An eight-month investigation by The Plain Dealer found that the national system that is supposed to protect the public from unsafe drugs does not work. It is failing because: The physicians- hired- by the pharmaceutical companies to test experimental drugsthe front line defenders against unsafe drugsat time endanger lives by de- parting from approved procedures. The overburdened, underfinanced FDA often closes its eyes to problems in the pharmaceutical industry because it lacks the skills, the staff or the stamina to do otherwise. The FDA rules and regulations of the past decade were developed by lawyers with strong ties to the pharmaceutical industry. The Reagan administration is intent upon dismantling some of the safety mechanisms incorporated in the drug regulation system. Physicians are no longer, the sole targets of evegrowing,_at times misleading, promotional campaigns of pharmaceutical firms. Prescription-drug advertising is for

1 '7 13 the first time being hurled at the American public through television and magazines, creating new problems for the FDA. Congress has done little to reform drug laws to help the FDA, but it regularly grants favors to the pharmaceutical industry. Scores of interviews and a detailed review of thousands of pages of federal documents and other reports reveal a pattern of wrongdoing among several major pharmaceutical companies. Pittman was only one of many -who have died nationwide during clinical experiments on newly developed drugs. The exact number of deaths is not available from the FDA. Some of the deaths may have been inevitable because the patients who volun- teered were terminal and viewed the experiments as a last resort. Others; however; may have died needlessly: For several, death came on the top floor of Wishard Memorial Hospital here, the spanking clean, quiet part of a public hospital that is home to Eli Lilly Clinic. Itis here that experimental drugs developed by Eli Lilly & Co. scientists are tested on human subjects. It was here that Pittnva and others agreed to enter a study on a drug called Dro- buline, a compound being tested for treatment of cardiac arrythmias: And it was here, several years after his death, that patient "HP" became a statistic in an FDA investigation of the drug-testing practices of Lilly, one of the world's largest, most profitable pharmaceutical firms. Pittman died Nov. 21. 1977, three days after entering Lilly Clinic. But, typical of the pace at which the FDA moves, it was not until_a year later=after a former Lilly employe complainedthat the FDA became aware of problems in the clinic's drug testing programs. A July 1980 FDA inspection report, released by the house government operations subcommittee on intergovernmental relations and human resources, stated a check of some patient records on Drobuline showed 70 percent had been given the wrong consent forms, which authorize testing and list risks associated with the particular drug. Patient !'FIHP" got the wrong papers; a two-paged form intended for healthy -volunteers. The first pagestates, "Compound 112092 (Drobuline) has been given only to animals so that you will be the first-subjects to receive this drug." The second page states, "you will receive no benefit from this drug, but you will provide us with information which is necessary for us to have before this drug is given to people with abnormal heartbeats." Pittman received 400 mg. doses; but after his death others in the program were lowered to doses in the 300-trig range: FDA records show even those levels were higher- than the maximum-200 mg, doses originally planned by Lilly and OK'd by the F-DA. A September 1980 memo from an FDA investigator to Dr. Frances 0. Kelsey, FDA director of scientific investigations, said his FDA review of the Drobuline trials suggested "a very early, perhaps premature start -up to the patient trials, the occurrence of adverse effects; patient deaths; a return to normal volunteer testing and an early termination of human studies; essentially without explanation:" "In March of 1978," the memo continues, "two events appear to-have resulted in an end to Lilly's Drobuline program, Having pushed the dosage of the drug to the limits of the patient's tolerance, and having demonstrated relatively unimpressive efficacy, Lilly now wanted to further increase the dose." Dr. Michael J. Hensley, the investigator who has since Left the FDA, then told of a patient who was released from the hospital on the 10th day of therapy; March 23; 1978. and suffered a fatal heart attack at home three hours Later: "Report of the death to the FDA was not made until April 20, 1978," Hensley wrote, and at -the time it was stated-the patient's response to the drug was said to have been excellent and no adverse effects werenoted." The doctor conducting the Drobuline trials was Alfred F. Fasola, a Lilly employe, who had tested a similar drug, Aprindine, which resulted in patient deaths in 1973 and 1974. In a November 1980 letter to Fasola; Kelsey said; "Information discovered during both the Aprindine and Drobuline inspections leads us to believe that you have repeatedly or deliberately failed to comply with the regulations relating to the proper conduct of a clinical study involving an investigational new drug." Kelsey cited violations of the Federal- drug code by Fasola, including failure to keep track of all the drug received and failure to maintain adequate, accurate case histories.

27-436 0 - 84 - 2 3 14 On Jan. 13, 19K1, an informal conference was held at the FDA to consider whether Faso la should be disqualified from participating in new drug studies. More than two years later, the FDA has taken no action on Faso la's case. As of last month he was still working at Lilly. The FDA will not comment on the status of this investigation other than to say it is in al.eyance. Lilly will not comment on any questions related to new drug studies; its clinic or Fasolarciting the continuing investigation as reason for its silence. Dr. Faso la could not be reached for comment, The Justice Department is investigating Lilly after the FDA charged that the company withheld information on patient deaths before approval of Oraflex, the anti-arthritis drug pulled off the market last year following reports of deaths in the United States and Great Britain. Some public statements from the firm have emerged, however, On Aug 9, 1982, after a congressional hearing on Oraflex and the drug approval process, Lilly's board chairman, Richard D. Wood, wrote his stockholders. He said charges against Lilly were unsubstantiated and that they were predicated on memo- randa prepared by operational-level FDA investigators. Lilly is not unique in its difficulties with experimental drugs, but it is one_of_the few companies with its own clinic for human testingmost contract with doctors who specialize in the type h ailment the drug is intended to cure. The testing procedure is very costly for firms involved and very lucrative for the tester, with many grossing as much as $1 million a year. The procedure has been policed by the FDA for many years with minimal success. Of 852 inspections of drug studies conducted by the FDA between June 1977 and last February, only 16% of the testing programs checked were found to be in full compliance with the law; according to the FDA Division of Scientific Investigations. Of the deficiencies found, nearly half involved informed consent and 35% involved inadequate drug recordkeeping. Informed consent problems can include understating the risks of the experimental drug or use of overly positive language on safety and efficacy. What is most disturbing, said Kelsey, is that inspections are conducted only on those studies selected by the companies as most thorough and favorable to their new drugs. "If these figures were compiled from the overall thousands or studies, the- percent- ages would be OK. But these are the basic reviewers that the sponsors finger as most reliable," Kelsey said. Kelsey is a legendary figure at FDA, She received a medal from President John F. Kennedy in 1962 for preventing the marketing in the United States of Thalidomide, a sedative that caused birth defects in the children of European women who used it. But there -is only so much Kelsey and her staff can do. A hodgepodge of FDA- written regulations governing clinical investigations are vague, lenient and cumber- some. And budgets are forever bding reduced. Like many other FDA employes, they may fall short of desired goals, not for lack of trying, but lack of time. In any -given three-year period. some 14,000 clinical investigations are involved in drag studies. The FDA can inspect only about 600 studies. Congress in 1977 gave the FDA the budget authority to increase the division staff ta 52. The highest it ever reached was about 40. This fiscal year it was lowered to 32. Kelsey said it would likely be reduced further. While reducing inspection staff, the FDA, to the delight of drug makers, is adding to the division that reviews new drug applications to speed up marketing approval. One of the biggest obstacles facing_Kelsey's staff is the FDA's lack of clout. Doc- tors often won't give them records. The FDA_h_as_na subwenapower. The FDA has disqualified 52 clinical investigators from further testing since 1964 and nine others have agreed to some restrictions on using investigational drugs. But the bureaucratic road- to disqualification -is not short. In the 1960's it took only about six weeks to declare a physician ineligible to test drugs. It now takes as long as four years. An informal hearing with the FDA commissioner has been replaced with a formal one, requiring participation of legal counsel for the physician and several FDA officials as well. "Thus we have three sets of FDA attorneys (for the bureau, forthe_hearing_officer and for the commissioner)," said Dr. Alan B. Lisook, chief of the agency's clinical investigations brandh, "all of whom are forbidden to speak to one another concerning the case on hand." The clinical investigator, meanwhile, can continue to study the drug until -a final determination is made. The FDA has the authority to immediately stop an investi- 49 15 gator from further study by citing a serious hazard to health; but this has happened only once. That was the case of Dr. Carl E. Blanck of Louisiana, who in 1977was given permission to receive a drug called-Anginin. It was to be for his personaluse, not for disbursement to patients, but FDA records show he administered the drugto more than 30 patients and could account for only about 7,000 ofmore than 20;000 tablets he had received. _Dr. Michael C. Gelfand of Maryland also was cited for keeping inadequate records, and "compromising both the integrity of the data and the safety ofthe subjects," according to his FDA rde. Although Dr. Gelfand did not deliberately violate the regulations, the violations were widespread and ongoing. Some of them,_ such as the failure to- keep adequate patient records containing crucial blood pressure and pulse rate data,are ineiccuS: able." reads the September 1981 decision of FDA Commissioner Arthur Jr. Hull Hayes But Gelfand had an outTitle 21,- Part 312 of the Food and Drug Law,which gives the commissioner the right to declare an investigator eligible ifadequate as- surances are made that the problem will not happen again. Hayes did exactly that "I conclude that although you have repeatedly failed to comply with theregula- tions governing exemptions for investigational new drugs,you have furnished adequate assurance that the conditions for exemption will be met in the future," Hayes wrote Gelfand. "Consequently, I have decided that you will not be disqualified from receiving investigational new drugs." The FDA has proposed further weakening the so-called IND (investigationalnew drug) regulations. The proposal, outlined in_the_Jane 9 Federal Register; articulates the flexibility available to clinical investigators to modify approved drugprotocols without_ telling the FDA. It allows drug researchers to conductnew experiments on drugs for other uses without getting FDA approval. Theie Would be limited,the notice states, to situations where- safety is not an issue and would be designed primarily for researchers in academic institutions whoare exploring new uses for marketed drugs. There is also a gap in the FDA's monitoring of drug experiments. It hasyet to publish regulations on sponsors of the studiesthe companies that hire the phySi: cians who do the testing: These regulations: which would make sponsors more responsible for the actions of their investigators, were first proposed in 1977. A notice in the same June 9 Federal Register said thesponsor regulations would be made final in the coming months, at about the same timeas the new regulations gciverning investigational new drug studies.

FDA OFTEN FINDS rrs HANDS TIEDPART 2 (By Judy Grande) WASHINGTON.Dr. Joseph Feldschuh, a cardiologist, is used seeing people die. Yet there was something especially disturbing about the dealths in 1979 oftwo heart patients. TeSts taken at the time of death showed unusually high acid levels in their blOOdlevels high enough to kill -even a person with_ a normal heart_ - Two_years_later, Feldschuh and a New York colleague were satisfied they founst_the cause of the acid_ overdose,a _particular brand of epinephrine,Abboject, (otherwise known as adrenalin), injected into the heart during cardiac arrest. The brand manufactured by Abbott Laboratories contained eight times the acid of similarproducts, -the doctors determined. They supported their finding with chemical analyses and a telephonesurvey of 38 doctors who had administered the_tlrug to _their_ ilatients. _ In June9)32._ the doctors _notified Abbott of their chilling discovery:. Of 852 patients in.New York City _injected_ with the Abbott brand, no survivor could be fciiiiid. The firm reacted swiftly _but silently. It reformulated the product to -contain- less acidused to stabilize the drugbut did not notify the U.S. Ftiod and Drug Administration. And it did notwarn doctors and hospitals of the potentially_ deadly danger. Nat until last Januam when a medical journal _published the findings by Felds- chuh and Raymond Gambino,a professor at Columbia University's College of Physi- cians and Surgeons; did Abbott recall the high-acid epinephrine.

ti 16 Abbott still denies its prodect was harmful, and criticizes the-testing methods used by the two doctors. It star is by its decision not to notify the FDA. Abbott is on solid legal grou id. 'fhe FDA, the federal agency responsible for keeping unsafe drugs off the market, claimed no jurisdiction. Because the manufacture of epinephrine predates the 1938 Food, Drug and Cosmetic Act, it escapes regulation. Beyond meeting with company managers to discuss the "voluntary" recall and telling them they used "poor judgment" in keeping the matter quiet, theFDA has done little, It considers Feldschuh's claim exaggerated and has taken few steps to find outif the product could have caused any deaths. "The FDA has no regulatory reason to try and reconstruct what may or may not have happened,''-said FDA spokesman William Grigg. Besides, said Grigg, the FDA has never received a complaint of this sort before. Because most cardiac arrest patients cannot be saved, doctors have said they might not suspect an additional factor in the death. "It's such a _dramatic charge (the 852 deaths) but its a moot point," spid Grigg. "Is it worth debating something that's been corrected?" Feldschuh and others think it is "If this is the way we're being protected by the agencies, forget it," said Felds- chuh, who is studying the new formula. He contends that it, too, r, have enough acid to kill. Though the Abbott-epinephrine episode may be unusual, it is typical of a common afflictionthe FDA's inability to keep close tabs on the pharmaceutical industry it is supposed to regulate. When health hazards occur the FDA is often the last to know. This happens not only after products are marketed, but during the drugapproval process as wellin part because the FDA is understaffed,overwerked and in some areas lacks the skills to handle the ever-growingcrises that confront it. As Dr. Peter B. Vaill, author of a 1982 study of the FDA's division of newdrug evaluation, said, the bureau works "in an atmosphere of constant distraction; tension and crisis." Vaill, professor of human systems at George Washington University who was commissioned- by the FDA to make the study, listed the "realities of everydaylife" in the FDA. To -name a few: Multiple conflicting outside interests with stakes in how the new drugevaluation process is conducted. Congressional scrutiny. Constant timepressure to keop approval on schedule. Decision-making responsibility for life and death. A history of skirmishing with the pharmaceutical industry, the media andvarious special-interest groups. Valli citedThe heavy dependence of this entire system on the nonprofessional secretarial-clerical staff to generate the system's actual, physical output,and the difficulty the professional staff has in seeking and adapting to this strategicfact." Those words soon came back to haunt the. FDA. In April 1982, the FDA approved the anti-arthritis drug Oraflex.Not- long after- wards, physicians were sent warnings from its maker that the drugcould cause kidney and liver problems in the elderly. Soon after that it was withdrawnbecause more than 79 people died while taking it here and inGreat Britain. Still being debated, nearly a year later, is what the FDA knew about thetoxic effects of the drug and when it_knew it. The FDA division that reviews new drugs had a six-monthbacklog in its mail- room. It is possible, FDA officials concede,that at least two reports of liver failure sat there unopened. Dr. Robert Temple, FDA acting director of New Drug Evaluation,cited cases of combined liver and kidney damage that the drugs manufacturer, EliLilly & Co, reported to the FDA before the drugs approval.. "One was containedin __the NDA (new drug application), one was provided as a desk copy to themedical reviewer and the other _two might well have not bien seen by anybody,"he said "They were probably in the document room." Each of the FDASsix drug evaluation divisions has a document room,where mail sorted from the central receiving office is sent for disbursal toappropriate individuals. ''There was at that time a six-month backlog in the document-room," said Temple.It is always difficult to hire people for the document room.They've had their grade knocked down twice. It's a position of considerableresponsibility, yet their grade is GS4 or 5 and salaries are low ($11,949 to $17,383)."

21 17

Temple, who said the backlogis down to one month_a,nd_may_soon be current he- cause the FDA is paying overtime to get the work done; did not try to defend the lapse. "One cannot argue that keeping things in your document room is good," he said. The FDA has a more general staffing problem, said Temple. It is often unable to get quality professional staff b-ecausemost people go into medicine to take care of patients. This is not exactly what they had in mind.' Yet, Temple said the FDA acted properly, given the information it had when it approved the drug. The FDA did not learn about the large numbers of deaths until last August; four months after approval, Lilly, however; may have known about them sooner; according to the FDA. The Justice Department is investigating whether Lilly withheld that information. Because of another FDA backlogin its computerized system for monitoring adverse effects from marketed drugsit was again among the last to know that a number of people were having fatal or serious allergic reactions to the painkiller Zomax. In March. Zomax was voluntarily withdravvn from the market because of five deaths associated with its use. In April, a House Government Operations subcommittee held hearings on the withdrawal and severely criticized the FDA's system of post-marketing surveillance. "Scarcely a week or a day goes by that most of us, here in this room and elsewhere across the country do not take some form of medication," said subcommittee chairman Ted Weiss, "I regret to report that I Mid the results of our investigation most disturbing, in that they very strongly indicate_fundamental deficiencies in the FDA's drug approval process arid adverse reaction monitoring and analysis system." Robert Eaton, an FDA pharmacist, told the House subcommittAT that as late as last February, one month- before the drug was withdrawn, the FDA- computer system has logged only- half of the more than 1,100 cases of allergic reactions to the drug. "Those reports could have been anywhere through the system," Eaton said. But perhaps more disturbingthe fact that as much as one year before the withdrawal, some FDA officials were aware of the dangerous allergic reactions, particu lady when the drug was used intermittently, as many painkillers are They met with the manufacturer, the McNeil Pharmaceutical subsidiary of Johnson & John- son, to discuss sending a warning- to physicians about the reactions. The warning about intermittent use was omitted. At the Zomax hearing, Commissioner Arthur Hull Hayes Jr. called the FDA'S system of post-marketing surveillance the best in the world. Hayes said that since coining to the FDA in 1981 he'd made ma_ny administrative and regulatory changes to alleviate some of the reporting problems. Further slowing FDA activity is the fact that employes in all divisions spend a tot of time away from normal duties to answer Freedom of Information Act requests. The FDA is the second largest recipient of such requests for information, led only by the Department of Defense. In -the first quafter of -1983, it logged-8,492 requests, a 4 percent increase over the previous quarter. In 1982, it cost the FDA $4.7 million and took 130 stafr-years to process the requests. Many requests are from pharmaceutical companies seeking_information on com- petitors activitiesor those of _their own firm. A lawyer who represents several major drug companies said it is cheaper for industry to file an FOI request on itself than to have one of its employes research the topic. The situation may worsen if Congress approves a bill requiring the FDA to notify firms before it releases any information about them. The firm would then have the opportunity to object. Gerald Deighton, staff director of the FDA's Freedom of Information division, said if predisclosure notification goes through Congress, it will cost the FDA close to $4 million more, take an additional 103 staff-years and double the time (it already takes several months) to get responses out.

FDA Is 8 YEARS LATE WITH DRUG EFFICACY REPORT-PART 3 (By Judy Grande) WASHINGTON-Stuffy nose sufferers know it as the "nighttime cold medicine" NyQuil, the dark green fluid billed as an antihistamine, analgesic; cough suppressant and decongestant all rolled into one. 22 18

It's the largest sell' ig over-the-counter cold product in the United States. And it may not work. A U:S: Food and Drag Administration advisory panel of scientists in 1976 labeled combination products such as NyQuil as lacking evidence of effectiveness because they contained too many Ingredients. While the report did not specifically name any combination drug, NyQuil fits that category because it has a combination of four active ingredients, and an alcohol content of 25 percent One of these ingredients the nasal decongestantis also individually listed as possibly ineffective when taken Orally. But seven years after the panel's report was published in the Federal. Register the official document of ',overnmental actionthe FDA is still dragging its feet on -a final ruling as to whether products like NyQuil are effective, whether they should be- reformulated or removed from the market This scenario is repeated with thousands of over-the-counter (CM products, all part of a massive, -first -time review of their safety and efficacy. Bogged down in 20,000 volumes of information affecting 400,000 products, the FDA is -eight years behind schedule and is not likely to complete its review until the year 2000. The man who developed the sluggish review process is Peter Barton Hutt, chief FDA counsel from 1971 to 1975. Although the FDA decided in 1966 to remove unsafe and ineffective OTC drugs from the market, the job was not started until 1972. Hutt had arrived by then: He designed a review procedure that allows corporate responses-at so many stages of the review that manufacturers can indefinitely swamp the FDA with information about their products. Hutt learned his trade as a partner in Covington & Burling, one of Washingon's most powerful law rims and one that has represented most of the major pharmaceutical companies. From there he went to FDA, where he joined a long line of FDA counsels trained in food and drug law by the very industry they came to regulate. Our lawyers go in and out of government all the time," said Hutt, who resumed his partnership at Covington & Burling in 1975 and represents the Pharmaceutical Manufacturers Association. In Washington, this is known as "the revolving door"the back-and-forth of men and women between cederal agencies and the firms they regulate. The FDA studied its own revolving door in 198h reporting on 297 senior officials who had left FDA the previous year. Of those, 8 percent went to regulated firms or are employed as their consultants. The FDA considers this a low percentage. But those figures do not include the agency's lawyers. Those numbers are harder to come by. The Plain Dealer round at least a dozen rormer FDA counsels who now represent the pharmaceutical industry, or did so before their stints at FDA. Several came from Covington & Burling, as did Hutt. His influence on the FDA and the drug industry appears as pervasive today as it was in the 1970s. Others include Richard Merrill twith Covington & Burling from 1965 to 1969), FDA general counsel from 1975-1977 and now dean of the University of Virginia law school, and Terry S. Coleman (with Covington & Burling from 1976-1981); current deputy general counsel for regulations at the Department of Health and Human Service% parent agency of the FDA. Hutt, a skilled orator and convincing debater, views himself as the prime example of the revolving door and makes no apologies for it. "What many in industry used to say to me was the only difference after I went to government was that they got the same advice, except it appeared in the Federal Register instead of an envelope from Covington & Burling," he said. But sometimes he finds his firm's influence embarrassing, as he admitted to a colleague recently A seminar was held a few months ago to train Senate staffers in rood and drug law. A panel discussion was planned with representatives of all the major industries regulated by FDA. The debate was hardly lively. Nearly every lawyer at the table had the same view of- regulation each was from Covington & Burling. "There is no question Peter Hutt is responsible by and large for the regulatory framework by which the FDA has operated for the past 10 to 15 years, 'said Thomas Grumbly, who was executive assistant to former FDA Commissioner Donald Kennedy. His conception of what FDA regulation is about is expansive." Regulation of the pharmaceutical industry dates to 1906, when Congress passed the Food and Drug Act. It called for protecting the public from hazardous foods, drugs, cosmetics and medical devices.

23 19 In 1962, Congress amended that act to require that all drugs be effective as well as safe, but it was not until the 1970s that the FDA commissioners began imple- menting the efficacy requirements for drugs marketed before 1962. It was also during the 1970s that the FDA hearing process- became more cumber- some, allowing long delays before the agency could take action against a firm or individual. Few dispute the worthiness of the safety and efficacy reviews Hutt designed,-but many, including consumer-oriented health organizations, blame him and other FDA lawyers for much of what troubles the agency today. Hutt designed the legal process for review of prescription drugs marketed before the 1962 drug efficacy amendments. Than too, is long overdue. Its schedule was set by -a- federal judge after several consumer health organizations sued the FDA to speed up the review. While lengthening procedures to give pharmaceutical firms due process in dealing with regulators, Hutt did try to streamline one regulatory area. In 1974, he hired a lawyer to rewrite the FDA's regulations for approving new drugsthe pharmaceutical industry's No. 1 priority. "His basic philosophy is the regulators would be better off if they were left alone with lawyers. Politicians will screw it up. Leave it to the guys who are the professionals," said onalawyer ofllutt. "He has an elitist view of what public policy is But he is a formidable opponent." Dr. Sidney Wolfe; head of the Ralph Nader-founded Health Research Group, puts it more simply: The FDA is caving -in to the pressures of the drug companies. "They started a procedure in 1972 that Should have taken four, five or six years," said Wolfe, a graduate of Case Western Reserve University Medical school. "The panels finished their work years ago, in some cases six or seven years ago, so it's all at the level of the FDA.- Hutt blames delay not an his_ procedures. but the unexpected amount of ingredients that had to be reviewed. He says it is a miracle it is being done as quickly as it is. Hutt, author of the textbook on food and drug law used in most law schools, de- fends the revolving door. "Everything I accomplished at FDA, in the matter of time in which I did, was accomplished because I had spent 12 years in training for the job," said Hutt. "A government that is as complex as this you have to bring in people who know something ahoat it." Hutt added that he wouli never presume upon a friendship at FDA: "That is the reason I never make a phone call or write a letter ... because that it seems to me is where the pubtic is entitled to be suspicious." Hutt numbers many at the FDA among his friends, including former commissioner Donald Kennedy. Perhaps more than anything else, it is these friendships that make industry lawyers so powerful concerning FDA matters. Friendships provide access where it might otherwis: not exist. And it provides an aura of trust and respect that probably would not exist in most adversarial s:tutations. It can work t his way: William Valra. formerly in the general counsel's office; is now with Arnold & Porter; a prenigicus law firm representing several major pharmaceutical companies. To getwifter action on the approvalof Pfizer Inc.'s new anti-arthritis drug, Feldene, all C odra had to was pick up the phone. A year ago he called J. Richard Crout, then director of the Bureau of Drugs, with whom he once worked; A memorandum of their telephone conversation written by Crout stated: "Mr. Vodra was trying to calm Pfizer but that the situation was getting worse and Pfizer was considering appeals to the bureau director and commissioner. He also said that pyroxicam 4Feldene) is being used widely in the political arena and before the McMahon Commission as an alleged example of agency ineffi- ciency." Vodra defended the call, saying he did not attempt to influence the FDA decision. The drug was already approved: It was merely a question of getting the final letter of approval out The letter was sent out about four weeks later. Vodra is the lawyer Hutt hired to rewrite regulations to allow new drugs to be marketed faster. But other priorities came along in the late 197-0s and Vodra never completed his rewrite. He said many projects he worked on until 1979, when he left, are only now coming to fruition. But delay is not the fault of lawyers, said Vodra. "It comes through a shifting of priorities, a demand for higher proof that what you're doing is correct and will abso- 20 lutely be defensible in courti_the zero defect mentality,_ the desire to do things com- prehensively instead of in _a_ piecemeal fashion. It has come from a desire to write in p I ain_ English_ instead of legalese:" The FDA chief counsel,-Thomas Scarlet, was brought to the-FDA-by Hutt. But Scariett could -not. be intervicsvcd_rar this article. By order_ of the secretary of the Department of Health and Human Services, the departinerit's general :.ounsel's office is no longer open to public scrutiny. It is closed to the press.

UNDER REAGAN, THE FDA Sims WITH INDUSTRYPART 4 One of the basic principles of regulatory reform is trust in the integrity of the private sector .. ."Chief counsel, U.S. Food and Drug Administration, 1982. "This administration has confused regulatory reform with no regulation."Drug industry lawyer, 1983. (By Judy Grande) WAsuiligaToN.The U.S. Food and Drug Administration, waving the Reagan banner of deregulaiion, i;as been steadily dismantling public safety programs that have been years, even decades, in the making. Whether sanctioning the use of drugs with known health risks or cutting down inspection stag, the Reagan-appointed FDA leaders have repeatedly sicici with industry instead of consum_ers on a variety of_heath issues. These actions come whihe opinion polls show irterest in health and medicine at all-time highs. A few examples: The FDA has cut in half enforcement actions, including seizures and recalls of adulterated foods-and drugs-The inspection staff has been reduced by 24 percent, from 1,183 in 1978 to 903 in 1982. The FDA has proposed streamlining the approval of new drugs to get them on the market faster. Opponents say this exposes patients and drug experiment volunteers to added health risks. The FDA shut down its antilkoties _laboratory, which tested batches of pills for quality and potency. The FDA is now leaving those judgments to the firms. The FDA scuttled a program that would have required manufacturers of certain hazardous drugs to supply informational leaflets with prescriptions. "The message is out The Reagan administration is not enforcing -the food and drug laws," said Dr. Sidney Wolfe,- director Of the Health Research Group, a consumer health- organization founded by Ralph Nader. The FDA- ha`- never been a model agency, but it is significantly worse under Reagan, said Wolfe. "There is an unprecedented number of instances of deferring to industry." Since 1981,_when President Reagan appointed former Sen. Richard Schweicker, secretary of Health and- -mast ServicesiHH_S),_the agency has backed away -from hardline regulatory_enforcernent. It strongly stressed instead the need for voluntary compliance, which gives firms an opportunity to correct deficiencies on a voluntary basis: An April 1983 report by the US. General Accounting Office (GAO) criticized this foi m of regulation, 'saying the FDA does not know to-what extent voluntary compliance is working. In three of the four cities where GAO reviewed inspect' wis, "no evidence was found in over half the cases toindicate -that investigators had followed up-on previously identified violations of the law and FDA regulations." Gommissioner Dr. Arthur Hull Hayes, Jr., appointed by Schweicker to head the FDA, disagrees strongly that formal enforcement actions are the only way to gp. "I think it is as fallacious to decide if waste upholding the Food,_ Drog_and Cos metic_ Act by the n_umlier of enforoementactions as it_is_ to decide if it is safe to walk in Washington by _the number of_ tickets given out," said Hayes. "I think one should also go out in the streets and look: Are there people that are sick out there; that are not being served? Are there drugs out there that are helping people? "It seems to me the test of whether the agency is doing its job is how well the public is being served. How well it is being protected." Wolfe and others say not very well. Among other examples, Wolfe j.aoints to the withdrawal of an HHS plan to put warning labels on aspirin bottles that use by children could cause Reyes syndrome, an ailment that strikes suddenly, causing vomiting and fever and in some cases, death. 25 21

There is reason to doubt -the reliability of the private sector, despite the belief of FDA counsel Thomas Scarlett that ". ..in most instances it can be relied on to safeguard the interest of consumers." In 1980, the FDA examined 7.118 domestically manufactured drugs and found violations of quality or labeling in 1,153 of them. In 1982, 6,410 samples were examined and violations were found in 1;061. Problems with imports are far greater, with as many as 70 percent of the drugs tested failing to meet U.S, standards. Some violations have, in the FDA's judgment, warranted criminal investigation. I:1980, the FDA banned a Smith Kline Corp. anti-hypertension drug bw:ause 60 deaths were associated with its use. It was later discovered the company may have suppressed data on liver damage. It is also investigating whether Eli Lilly & Co. withheld information on deaths associated with the use of Oraflex. "This administration has confused regulatory reform with no regulation," said William Vodra, who worked in the FDA counsel's office in the late '70s. He now works for the law firm of Arnold & Porter, and represents many drug companies. The drop is enforcement is being perceived by the drug industry as ordered by Reagan. What can happen is they start taking bigger gambles. They, after all, might not get caught," Though the FDA denies it has ordered a slowdown in enforcement activities, it is the perception that counts, said Vodra. The FDA is a mature agency. It can read election results as well as anybody else. Nobody has to tell them Ronald Reagan wants less regulation. If Ted Kennedy is elected in 1984, you don't have to send Telexes (teletyped reports) to the fields to start en forci ng." Another major concern of consumer groups,- including the American Public Health Association, is the plan to streamline the drug approval process. These recently proposed regulations would reduce reporting requirements on drug studies, accept foreign data as a sole basis of approval of a drug, tighten time frames for agency review of new drug applications and give much greater freedom to physicians who test drugs during the early phases of human research. "Rather than the approval of new drugs, we believe the FDA resources should be directed toward removing ineffective prescription drugs from the market, and expe- diting the interminable over-the-counter drug review,the American Public Health Association wrote to Schweiker in February, just before he left government. Schweiker, however, considered these regulations to be the most significant reform in the drug laws since the 1960s, They were among his last official efforts. The pharmaceutical industry has sought such reform for years, but its spokesmen say the FDA has not gone far enough toward relieving industry of the financial and regulatory burden of developing new drugs. The industry says it costs $70 million to develop a new drug and takes about three years for the FDA to approve it. A November 1981 GAO report, however, estimated_ average approval time by FDA was down to about 11 months for important drugs (those offering breakthroughs in treatment) from 17 months in 1977; In addition, drugs that offer significant therapeutic advances have been on a fast- track approval system for some time, negating the industry's position that important drugs are being kcpt off the market. Accutane, Hoffman-LaRoche's advance in the treatment of acne, was approved so quickly earlier this year that the firm that was not ready to market it. Of 27 new drugs submitted for approval in 1981, only two were classified by the FDA as providing important therapeutic gains and 1/ as modest therapeutic gains. More than half the time was spent reviewing applications for drugs the FDA considered of- little -or no therapeutic gain. The FDA has made drug approval a priority. It has reduced staff in other divisions, such as inspections, while keeping the drug evaluation division stable. In 1984, the FDA plans to reallocate 35 staff years and $1.2 million from "lower priority activities" to the new drug division. The acceptance of foreign studies as proof of a drug's safety and efficacy is also a concern to health groups because the FDA has no authority to monitor studies in other countries. Timolol, a drug for high blood pressure, was approved recently on the basis of a Norwegian study. Robert Temple, acting director of New Drug Evaluation for the FDA, agreed there are legitimate concerns about using foreign data, but added that the new regulation only says the FDA may accept it. 22

Ilayes said the FDA is developing a drug approval policy that "assures safety and efficacy by today's standards but allows us to do that in a well-ordered way so that safe and effective drugs are developed, reviewed and approved and get on the market to patients where-they are needed as quickly as possible." Hay& also plans to define effiCacy for the first time Under the 1962 amendment to the Food, Drug and Cosmetic Act, drugs were required to be effective, as well as safebut Congress did not define efficacy. FDA criticsfear Hayes is going to lower efficacy standards. Reagan; during his campaignin 1980, backed repeal of the efficacy requirement, a step even drug companies opposed. But Hayes said he is not attempting toreduce the standard, only provide awork- ing definition for the FDA. Some, hoWever, say it is too late. Rep. L. Fountain, D-N.C., before he retired from Congress last year cited the approval of Feldene as an example of lessening efficacy requirements. Feldene is non-steroidal drug for arthritis, which the FDA said is no more effective than aspirin and may have- additional side effects. But Temple; who has the final say on_ all ]rug_ approvals,_said, "The law is clear. You have to prove- a drug is effective for its purpose. It does not say it has to be better. It can even be worse," Thiiie are but a feW of the changes brought about by- the Reagan FDA; most of which were recommended by the drug industry. The changes are not cost-saving measures made by a financially strapped federal agency. Instead, they save money for one of the world's most profitable industries. Shutting down the antibiutics_testing lab is one example. Most of its cost was paid for by the drug manufacturers, not the FDA. The manufacturers expect to save several millions of dollars. The pilot program to give out information leaflets to patients on drug side effects also saved the government nothing-It was eliminated, despite a 1982 survey by Chil- ton Re- 'arch Inc. in which nearly 70 percent of consumers surveyed said they were not told about_precautions and possible drug side effects by their doctors. But drug industrialists and pharmacists strongly objected to theproposedpatient package insert program; saying it would laeloo costly for the manufacturer, too time Consuming for the pharmacist and too frightening for the patient. The FDA commissioner bought that argument and said _a citzens group should handle thetask ofbetter informing consumers. Thus; the National Council on Pa- tient Information and Education was formed. Its first major effort was to enclose a message on the proper use of prescription medicine with the July 1 checks to the nation's 36 Million Social Security recipients. Who paid for the printing and mailing? The taxpayer.

FDA IS DWARF AGAINST GIANT DRUG INDUSTRYPART 5 (By Judy Grande) WASHINGTON- -The pharmaceutical- industry spends $2 billion a year to promote its drugs. The U.S. Food and DrugAdministration spends about $1 millionto make sure the promotion is truthful. Pharaceutical firms place 20,000 advertisements in medical journals each year The FDA has_time to_scrutinize only 500 of them. Pharmaceutical firms in 1981spent $630 million on sales agents who hawk pills to physicians; That is nearly twice the size of the entire FDA budget. The FDA, the only federal agency mandated to_prbtect_the public from unsafe drugS, is a regulatory dwarf amid pharmaceutical giantsmutspent, outnumbered, and often outmaneuvered by the industry it is supposed to control. The division of drug advertising and labeling is particularly hard - pressed; with its cadre of five scientists who try to review the advertising andpromotional campaigns of more_tban la(Lpharmaceutical firms. The task become_more difficult each year as companies find new waysto peddle their productsfrom lectures, slide shows and seminars to telephoneconferences, video sessions and home computer& Competition in the drug industry is fiercer_ e_vety day as more and morejroducks come on the marketplace. In 1981; consumers spentU4.2 billion on prescription drugs,anincrease of12 percentfrom the year before. Lastyear 1.5 billion prescriptions were filled. 23 With the heightened competition comes an ever-increasing bending of the rules, said Lloyd G. Millstein, Ph.D. acting director of the FDA's drug advertising and labeling division. Making Millstein's task as industry watchdog more difficult is the FDA's after- thfact role. It cannot pre-clear ads. It can only act if promotions are misleading or untruthful. They sometimes ore. From October 1982 through February 1983, the FDA skimmed over 8,000 ads and 3,000 promotional pieces. Of those, 300 were monitored in depth. _The result: 170 regulatory actions, ranging from minor to serious violations, and 85 ads and promotional pieces canceled. Some are resolved quickly by agreement with the firms,_said Millstein, who worked i.e.- the drug industry for 20 years. Others take more time. It took six months for the FDA to settle a dispute over Pfizer Inc.'s promotional campaign for an angina drug called Procardia. The FDA called the promotions false and misleading, "based on untruths, partial truths and omitted information" and said it increased the risk of serious adverse reactions to patients. The FDA concluded that side effects were understated, benefits were overstated, and it was advertised for a use for which the drug was not approved. "This misleading campaign comes at the particularly crucial time of first introduction of nifedipine (the generic name of Procardia) to many American physicians who are not yet familiar with_the important precautions they need to know in order to use the drug safely," the FDA wrote Pfizer. The violations were discovered in April 1982. It was six months before Pfizer sent a letter to doctors stipulating the FDA's objections and correcting its promotion of Procardia. The FDA said it had no way of estimating how many patients were put at risk in the interim. The FDA lacks authority in another important areathe distribution of press releases. "We don't regulate -press kits. It's against the First Amendment, unless it is used for promotion,' said Millstein. "As long as it is not false and misleading there is nothing we can do." But more and more press releases to announce new drugs have the effect of promotion, as opposed to news. When Eli Lilly & Co. introduced its new anti-inflammatory arthritis drug, Ora- flex, last spring, more than 6,500 press kith were sent out touting the new drug and its possible revolutionary ability to regress arthritic disease. It sold a half million prescriptions in its first 12 weeks. But there was not evidence that Oraflex would treat the disease. The FDA sent out a so-called regulatory Letter _to stop the promotion. By that time, Oraflex had been pulled off the market because of more than 70 deaths associated with its use here and in Great Britain. It takes months, often years, for the agency to take any regulatory action, unless there is an obvious imminent hazard. With Oraflex, the deaths were not immediately known by the FDA. The regulatory letter was aimed only at the false claims about halting the disease. But because of those claims, Millstein said, "it sells that many more prescriptions and that many more people die." A similar promotion problem occurred with Feldene, also approved last year for relief of arthritic pain. The FDA told Pfizer, Feldene's manufacturer, that its press kit was misleading, saying it falsely claimed Feldene was superior to aspirin, and that it may have a beneficial effect on the disease process. "In light of the complaints made by your company concerning the_ press Release and subsequent publicity concerning a competing product _(Oraflex); we find the information contained in your press release surprising," the FDA wrote to Pfizer. The FDA tries to monitor numerous other areas, including teleconference and video sessions, where groups of physicians sit down together to discuss a particular product used in their medical specialty. This poses another problem for an already overworked division: how to keep track of every call made or tape sent by industry to doctors. One problem with the Pfizer promotion of Procardia, dealt with a videotape fea- turing flve prominent cardiologists discussing uses of the drug. Despite the severity of the disease for which the drug is intended, the videotape contained no precautionary information, such as the drug's ability to cause "profound hypertension," the FDA wrote to Pfizer. 24 In addition, a Harvard Medical School cardiologist suggested Procardia was useful for heart attack patients. a claim not approved by the FDA. The Pharmaceutical Manufacturers Association (PMA), which represents 145 firms; says the purpose of advertisements and other promotional efforts is to provide physicians with information after the need for a product has been determined, not to promote use when no need exists. The PMA has a code of marketing practices pledging members to "provide full scientific information with scru_pulous regard for truth in all matters." The PMA says it has reason to comply with the FDA's regulations because its products are subject to seizure if they disobey the law. FDA records show, however, that at least a third of the nearly 500 seizure actions approved from 1979-1981-resulted in no products seited. This stems from the FDA's inability to detain drugs produced in the United States. A recent report by the U.S. General Accounting Office said that by the time the FDA got approval from its counsel's office to seize the products, drugs found to be in violation were already shipped to the public. Amid these difficulties; there is perhaps a larger problem looming. Many pharmaceutical firms are taking their campaigns directly to the consum- erthrough television and magazines - Realizing the potential for trouble, FDA Commissioner Dr, Arthur Hull Hayes, Jr. has asked for a moratorium until the FDA has a chance to study the issue. The FDA will test consumer reaction in_ Tour citiesCleveland, Buffalo, New Or- leans and Seattle. Volunteers will view simulated TV ads for prescription drags or read magazine ads,and then fill out questionnaires. At a recent public meeting of health professionals, Ciba-Geigy Inc. presented to Hayes a mock TV ad for Constant T, a drug for bronchial asthma. "It can help you forget about breathing, so you can start living" said the voice on the TV set. This informal approach is familiar to consumers of over-the-counter drug products that come under the jurisdiction of the Federal Trade Commission. But prescription drugs carry more serious side effects. "When Congress wrote-the law (in 1962) it assumed advertisements would only be directed to the doctors. They never thought otherwise,' said Milistem. "Now Con- gress is in a position to answer industry's question: 'Why- can't we?' " Hayes said fundamental questions have to be answered before a decision is made, "What is the advertising for? Who will it serve? What is its purpose? Who will it help? And who will it hurt?" The FDA approved, on a -trial basis, direct advertising on Cable Health Network, a nationwide cable -TV service. It began last month. Joe Boyd, CibaGeigy's director of public relations, said the industry's interest in diree. advertising to consumers stems from the public's desire to take a more ag- gressive role in health care. Advertising in the mass media, instead of in medical journals alone, should benefit consumers by making them aware of different therapies available, said Boyd. It would also make them aware of products that benefit the companies materially. Ciba-Geigy, however, has made no firm decision yet on direct-to-consumer advertising. There has been a breach of the voluntary moratorium by a British-owned company, Boots Pharmaceuticals Inc., which is advertising its arthritis drug, Rufen, in Florida. Boots is running a TV commercial stating that Rufen is cheaper than Upjohn's Motrin, the identical drug. Boots has also taken out ads for Rufen in several Tampa area newspapers. Upjohn has filed a complaint against Bdots, which the FDA is reviewing. "They are flouting the moratorium in our face," said Milstein. But consumer advertising seems to pay off, Last year, Bo is advertised a $1.50 rebate with Rufen prescriptions and received 19,000_ rebate coupons within 14 months.- It has captured 8 percent of the market for that type of drug: Health professionals are worried, however. Some say it will- lead to- overuse and addiction.- Many say consumers will not be able to understand the risks associated with the drugs. The American Association for Retired Persons and several consumer health groups are flatly dp_posed to direct advertising. Even some companies are concerned. A representative of Merck, Sharp and Dohme said its concern is that some health decisions call only be made by qualified professionals. If the concept is approved, the Merck spokesman said; companies should voluntarily preclear ads with the FDA:

2J 25 Doctors have not responded fiivorably W the idea yet, either. Surveys have shown that 70 percent oppose consumer advertising because it may put undue pressureon them -to prescribe a certain heavily advertised drug. But the American Medical As- sociation has not yet taken an official position, saying it is still studying the issue. Former Sen. Gaylord Nelson, who held many hearings on the pharmaceutical industry in the 1970s, is not wavering. "There would_ be tremendous pressure on physicians if direct advertising to consumers is permitted. And what is the purpose of it? The only conceivable purpose is to expand the unncessary use of prescription drugs. It's on open invitation to the drug industry to really corrupt the public. If the American medical profession is worth a damn it ought to be up in arms about this. If the FDA and the -AMA don't come out strongly against this, they're selling out to special interests. That's all there is to it."

DRUG INDUSTRY WIELDS POWERFUL POLITICAL CLOUTPART6 (By Judy Grande) WASHINGTON.FormerSen. Gaylord Nelson of Wisconsin tried for eight years to sever the ties between the drug industry and the doctors hired to test drugs before they get on the market: Nelson, a popular, respected Senate Democrat, could not persuade his fellowsena- tors to break up what he said was an unwholesome relationship between drug milkers and drug testers. His bill never even got a hearing. Nelson got plenty for his troubles, though. Drug firms contributed $4,750 to the campaign of Rep. Robert Kasten who defeated Nelson in 1980. Nelson got no drug company money. This year Kasten proposed a product liability bill that has the drug industry's enthusiastic endorsement: The pattern is familiar. Recently, Congress has done little to protect the public from unsafe drugs, but quite a lot to protect the pharmaceutical industry. Despite repeated attempts, no major drug reform bill has been passed since 1962, when the late Sen. Estes Kefauver of Tennessee successfully_fought for amendments requiring drugs to be effective as well as safe. Since that time, Congress has repeatedly failed to reform the nation's drug laws and give the U.S. Food and Drug Ad- ministration (FDA) greater power to enforce those laws. Among the failed attempts: Congress did not pass a 1976 bill that would have placed restrictions on promotions by drug sales agents-and a an on gifts and samples to physicians. Congress rejected in 1979 legislation requiring drug firms to conduct post-marketing and scientific investigations of approved drugs and would increase the FDA's authority to impose civil penalties. The same_bill would have given the FDA subpoena power and ailthority to order drug firms not to distribute questionable drugs. Bills seeking this detention authority were submitted in each Congress from 1974 to 1980. Congress never even considered a -1980 bill that would have required the dissemi- nation of infomation on the risks of drugs on pregnant women. Congress has however, several times in recent years granted tax credits and incentives to an industry that is already one of the most profitable, and last year failed by only five votes to extend by as much as seven years the 17-year patent rights on drugs. Pharmaceutical company supporters have also attempted; though unsuccessfully so far, to repeal Kefauver's drug efficacy requirements. This year even before the 98th Congress was-in full gear, drug company lobbyists were back swarming on Capitol Hill, trying to new sponsors for the patent bill and others that would add to the firms already impressive bottoM line. And as in years past, members of the House and Senate responded quickly to the call of the companies that contributed more than $750,000 to the 1982 congressional campaigns. _Sen. Charles McC, Mathias Jr., R-Md., has reintroduced the patent bill and has held the first of two hearings before a Senate Judiciary subcommittee. The Mathias bill, which breezed through the Senate by voice vote in 1981, would allow seven years of additional patent protection for manufacturers-whose drugs are subject to federal regulatory review. Companies contend that the FDA takes so long to approve new-drugs that patent life is nearly gone before a drug gets on the market. This stifles innovation and leads to decline in research, they say. And, like the 1981 bill, it applies to all manufacturers undergoing_pre-market proval of drugs. The House version, sponsored last year by the liberal Rep. Robert

4 26

Kastenmeier, D-Wisc.,was not retroactive. It applied only to thosedrugs for which patents were obtained after enactment of the bill. "Lobbying on this bill (Kastenmeier's) was one of the most intense I've seenin Congress. It seemed everybody had a personal friend working for one of the companies,said one House member involved in its narrow defeat, who asked not tobe named. "The drug companies are quite powerful. It's really that simple.Aside from contributions, they can arrange lots of speaking engagements. They have 10 or so ex- ecutives Sitting in a room. You say a few words and you_get $1,000." But the Kastenmeier bill, which, because it was brought up under a suspensionof the rules needed a two-thirds majority of the House to pass, fell shortby five votes. This year,_he stayed away from the bill. His former subcommittee counsel, Bruce Lehman, said Kastenmeier wasdisgust- ed. Tremendous personal press_ure was put on him by the oppoSition,which included the generic _drug industry, consumer groups and a few of his liberalcolleagues, said Lehman. He was burned out He wanted to spend_moretime,on important things" After a brief search, the drug makers found Rep. Michael L. Synar, D-Okla, a member of KaStenmeier's subcommittee, who would carry their flag, He is drafting a bill said to be almost identical to theSenate version, including the industry-supported retroactivity. Besides Nelson, there are a few other congressmen who, over the years; have taken on the pharmaceutical industrySen. Edward M. Kennedy,D-MaSii., Rep. Albert Gore, D-Tenn., Rep. L. H. Fountain, D-N.C., and at times, Rep.John Dingell, aMich., and Sen. Howard M. Metzenbaum, _ At the Mathias patent hearing last month, Metzenbaum argued that government regulations to insure drug safety and effectiveness do not unfairly eat awayat patent life and decrease incentives to create new drugs. "The pharmaceutica, makers claim fewer and fewer drugs arebeing approved. As we will see, this is hogwash," MetzenbaumsaidThe rate of drug approvals has gone up; not down, in recent years, _ "The drug companies themselves predict-that their market will triple in10 years to a total of $217-billion in annual sales worldwide. Is there not afantastic spur to innovate in itself?" But behind the patent bill, which opponents argue will _cost consumers moreby keeping cheaper generic imitations off the market, -is thePharmaceutical Manufac- turers Association, which last year spent about $200,000- forCapitol Hill lobbying. The PMA has also hired big_names to tout its cause, with the leaderbeing Peter Barton Hutt, a respected former general counsel of the FDA, who representsmany major drug companies. The induStry has also tied itself to big-name Democrats, includingthe influential law firm Manatt, Phelps, Rothenberg & TunneyManatt being CharlesManatt, national chairman of the Democratic party. The firm was hired tolobby on behalf of the drug industry. Central to the debate is the issue of drug laghow long ittakes the FDA to approve new drugs for marketing. Congess became deeply involved in that issue as well last year,forming the Com- mission -on the Federal Drug Approval Process. But the commission report, a consensus document ofvolunteers from industry; academia and a few consumers; was little more than anindustry wish list. It contained most of the recommendations industry has made over the yearsto streamline the drug approval process. The commission was funded by- Project Hope; a charitable_organizationactive in health care overseas and in health issues domestically. Itsboard chairman is W. H. Conzen, former chairman of Schering-Plough Corp., a NewJersey-based pharmaceutical manufacturer. The pharmaceutical web becomes more tangled whenconsidering who lined up Project Hope to fund the commissionJonah Shacknai, formeraide to Rep. James Scheuer of New York, who_setiip the commission with Gore. Shacknai has since left governroent to open his own law firmand now represents several major pharmaceutical firms. Gore, a leading opponent of patent extensism,hallenged_c someof the commis; sion's work but did not interfere with the report, saidThomas Grumbly, Gore's former staff director. _Grumbly, who was executive assistant tb former FDACommissioner Donald Ken- nedy; said the public did not pay for the study, exceptprinting costs, so it was not appropriate for Gore to dominate the commission. Congress has not been lax in one areaholding hearings. 27 Dozens of hearings have questioned why particularly dangerous drugs have been approved by the FDA and why the government's safety system fails. But few result in significant legislative changes. Fountain, who retired last year, pursued the hearing format and was responsible for some administrative changes at the FDA. His successor as chairman of a government operations subcommittee, is Rep. Ted Weiss, D-N:Y. He appears to be following Fountain's footsteps, having held a hearing on the painkiller Zomax, recently withdrawn from the market because of fatal allergic reactions. Rep. Mary Rose Oakar, WO, of Cleveland, recently held a hearing on drugs and the elderly that was highly critical of the FDA's system of drug protection. Oakar said she was pressured by colleagues, as well as the pharmaceutical industry, to drop her hearings. MS. DAKAR. Thank you, Mr. Chairman. Mr. PEPPER. Thank you very much, Ms. Oakar. My Florida colleague now, Mr. Bilirakis. STATEMENT OF REPRESENTATIVE MICHAEL BILIRAKIS Mr. BILIRAKIS. Thank you, Mr. Chairman._ I too, sir, would like to congratulate you for calling this most lin, portant hearing, and to commend Ms. Oakar for suggesting itI would also like to commend the Thompson Medical Co. representatives for appearing and being willing to serve; I personally was disappointed when we recently joined with the Senate to hold the hearing on the misuse of drugs, and the pharmacy companies were not represented; I thought that was pretty terrible; and I was very disappointed. So, I commend Thompson for appearing. This subject matter is a serious concern to me, as I represent the fastest-growing area in the Nation when it comes to senior citizens. I should add their primary concern is health care, of course. I feel that this hearing will provide us with much needed information at a time when many Americans are concerned about drugs that they can purchase over the counter; not only for the efficacy of the product, but also its safety. Though this hearing is certainly_geared in another direction, we, Mr. Chairman, must not forget the recent tragic events that have taken place withI sometimes thinktoo easily available over-the- counter drugs. Health-related professionals, including doctors, nurses, and _phar- macistsand we prepared for this hearing by going to- the grass- rooth, by contacting personally medical doctors and pharmacists and others in our area to help us get together some of the prob= lemshave all expressed their concerns with over-the-counter drugs. They expressed concern that a great misuse does take place as many of our citizens do not bother, as Mr. Regula mentioned, to read the instructions. They often misunderstand them and still others cannot read or comprehend the instructions. I feel that I should also mention the growing concerns of many professionals over nonprescription drugs being sold in grocery stores; self-service operations; and even hardware stores. These drugs are purchased there to save a little bit of money, since the price of prescription drugs is often too_ expensive for a limitcA budget and many times is not tax deductible.

32 28 The alternative_ is over-the-counter drugs which are not always as effective and often do not work with the efficacy that prescribed medicine usually does. Mr. Chairman; I'd like to bring to your attention and to the attention of the listening audience a survey which was recently conducted in my district by Operation P.A.R. [parental awareness and responsibilityl; a group which ordinarily deals with the misuse of drugs by youth. But this survey clearly indicated more than 50 percent of the elderly persons, those 60 and older; who were surveyed; were taking medicine in a dangerous manner. According to the survey, 49 percent of the survey participants use over-the-counter drugs; 44.5 percent of them use them with prescribed medications. Seventy-one percent never or only sometimes consulted their physicians when using over-the-counter drugs. Mr. Chairman, I could continue but time certainly does not allow it. Thus; I ask your unanimous consent that the entire survey be submitted for the record, and I commend its results to the committee. Thank you; Mr, Chairman. Mr.PEPPER.Without objection, it will be received. 'See app. 1, p. 223 for material submitted by Representative Bilir- akis.] Mr.PEPPER.Mr. Lantos. STATEMENT OF REPRESENTATIVE TOM LANTOS Mr.LANTOS.Thank you very much, Mr. Chairman, First; Mr. Chairman; it's an enormous pleasure for me to commend you for your unceasing efforts on behalf of our Nation's elderly. May I just say, parenthetically and privately, that I saw you at 10 o'clock last night on the floor of the House when we concluded the MX debate. I understand you were up at 5:30 this morning to appear on a network television program. If you will just tell us what OTC medication you are using, I think we 11 all be way ahead. Before _I make a couple of comments of a substantive nature, I want to apologize; Mr, Chairman; that I am to give a brief testimony on the Senate side and will be back right after that These are enormously important hearings, and I view my respon, sibility as a professional economist of putting them in some kind of perspective. They are analogous to hearings relating to highway safety or airline safety, because they deal with human tragedy; To- morrow another subcommittee of the House will hold hearings on airline safety in San Francisco, and we will be focusing on the trag- edies that occurred during the last few years with respect to airline safety. Yet, At the same time we'll be focusing on the fact that the overwhelming bulk of Americans who use air transportation have open to them a whole new arena of public service by safely and comfort- ably and relatively inexpensively using a means of transportation that, in a different generation; was just dreamed of. I think we have a similar problem with highway safety. Fifty thousand individuals are killed on- our highways each year; Mr. Chairman; and I think every one of those represent§ an enormous human tragedy. Yet, we are not talking about terminating the use 29 of the automobile. What we talk about is developing safe highways; safer automobiles; better-trained drivers. And I believe itcritical that in dealing with over-the-counter medicines we differentiate between the use by millions of Ameri- cans of safe and effective over-the-counter medications and the fly: by:night Companies which put on the market with irresponsible advertising dserous- products and the problems that are created by user misuse, ribuse, ignorance. I was intrigued at our last hearing, Mr: Chairman; that many of the problems we discovered in dealing with prescription medications are of course, applicable to over-the-counter medications, and they are generic in characten For instance; taking 5 times, 10 times, 100 times the prescribed dose. It has yet to be explained _to me how there is a difference between a consumer taking an overdose of a prescription medicine and the consumer taking an overdose of a nonprescription medicine. If the problem is more effectively designating on the label the proper dosage, this is a generic problem which I think is equally applicable to both. I was very much impressed; Mr: Chairman; by the problems that stem from mixing of medications. But you can mix prescription medicines with prescription medicines, over-the-counter medicines with other over-the-counter medicines. You can cross-mix. And I think the problem, again; is generic. I will be very much interested in what we economists call; a cost- benefit analysis: If; in fact, there are x number of individuals who, in fact, suffered by taking medications or abusing medications, whether it's prescription or over-the-counter drugs; I'd like to put that in the statistical framework of the tens of millions who benefit from this. In your opening remarks; Mr: Chairman, you talked about Contac. Don't take away my Contac. I use it several times every year when I have a cold and I would deeply resent having to go to a physician to obtain Contac, which today I get atthe drug counter at Safeway and I suspect along with millions of other Americans; it gets rid of my cold very fast; Our grandchildren are using cough medicines. I looked at the labels of those cough medicines and those cough medicines_contain PPA. I would hate to see that cough medicine taken away from my grandchildren just because there may be anecdotal experience of adverse reaction to PPA by some But I'm really suggesting, Mr. Chairman; that we have got to conduct our investigation, as I know you intend to in a broad framework, recognizingthat if, in fact; tens of millions of Americans like myself take over-the-countet medications, from cold medicines to diet medications to cough medicines, we must give some credit to their intelligence; We must give some credit to the intelligence of the parents and grandparents Who allow children to take cough medicines, because there clearly are no adverse side effects: If there were we would stop doing this And because the benefits are self:evident. Finally, Mt. Chairman, I think we have got to give the FDA at least the degree of fairness in our approach to them. These are honest public servants who are likely to be making far more money in the private sector, who have chosen to dedicate their profession-

27-436 0 - 84 - 3 30 al expertise to protecting the public health, and _to suggest that there is some strange conspiracy between the FDA and other ele- ments in society allowing the FDA to go ahead with the use of unsafe drugs raises some serious questions in my mind. I thank the Chair. Mr. PEPPER. Well, thank you for your very informative statement, Mr. Lantos. Next, Mr. Daub. STATEMENT OF REPRESENTATIVE HAL DAUB Mr. Daus. Thank you very much, Mr. Chairman. I will be brief. I'm going to first attempt; because I have such great respect-for our chairman and for the leadership of my ranking member, Mr. Regula, and because I appreciate the innovative, as always, and constructive, efforts that my good friend, Mary Rose Oakar; makes; particularly since we give her credit for this hearing, to pronounce the word that you've all been hearing a description of, called PPA. I had trouble with it and I tried. So, 'thought before we get started with our panel, who has been so patient, that I would attempt to pronounce that word: phenylpropanolamine. Did I come close to pronouncing it correctly? But now you may know, if you don't, in the audience what we were talking about, and indeed, I hope I came close. But PPA. I too; Mr_Chairman; am very concerned about insuring the safety and efficacy of over-the-counter drugs such as PPA. Howev- er, with all due respect, -I Question some of the methods that can be used to focus on this issue; Bringing up extreme cases regarding adverse reactions from the use of, for example, ETA, in front of TV cameras and other media, can be misleading and create misleading impressions when dealing with this area of _concern; It is our duty to highlight possible dangers, particularly with this committee's jurisdiction, in order to protect our senior citizens. But we must take care not to resort to scare tactics to accomplish this and; indeed, if we're not careful, we could engage in counter-productive results. Such scare tactics would encourage those who are using drugs safely and efficiently and effectively for more important purposes to abandon that safe and appropriate use. This type o- concerning the safety and efficacy of drugs should be dealt with in- a scientific arena during an oversight hearing with experts testifying, And I'm glad to see that some of theexperts will be included in -the hearing; Virtually anything taken in excess will have negative effects. PPA, too, when used in ways other than those authorized and/or written in terms of label instructions; could; indeed, be dangerous; Appropriate labeling requirements are important for over-the- counter drugs, and I'm glad to see that this subcommittee will have the opportunity to review current labeling on the OTC drugs. In addition, it is important to insure that the Food and Drug Ad- ministration is not lax with respect to its duty of insuring that the safety and efficacy of drugs be maintained for our citizenry at large. Regarding PPA, the FDA approved this drug as safe and effective afthr 4 years of reviewing the literature and the data on the

30 31 drug. They approved it pending further study, and I think the record should show that, and they have since that time asked -for new research on aspects of the drug that are being questioned. This is an important issue for our elderly population. As you've already heard; of- the noninstitutionalized elderly; 70 percent use over-the- counter drugs compared to only 10 percent of our general population. It is my hope that this hearing will highlight the importance of appropriate labeling requirements and work with the Food and Drug Administration authorities in approving the over-the-counter drug, I think, proliferation that indeed, simply because of cost and great scientific research, will be an even greater part of our marketplace in the future. And, indeed, with our help we hope that this combined effort will be with consumer advocates a very responsible approach. I want to thank all of the witnesses who will be testifying today. We have, indeed, an impressive list of witnesses. And I look forward to hearing their testimony and, again, want to particularly thank, Mr. Chairman, Ms. Oakar for her leadership in this matter. Mr. PEPPER. Thank you very much, Mr. Daub. Now we have a very outstanding panel of over-the-counter con, sumers and consumer representatives. I will call their names and then they will come forward. For overview, Dr. Sidney Wolfe, director, Health Research Group; president; Public Citizen; a nonprofit citizens' organization founded by Ralph Nader. Mrs. Anthea Sacks of Westport, Conn., Ms. Gloria Jean Davis of Albany, Ga., Mrs Janey Phipps; resident nurse, of Gray, Ky., and Mrs. Kathleen O'Reilley, consumer expert, National Broadcasting Co. First we'll call on Dr. Sidney Wolfe. PANEL IOVER ,THE-COUNTER CONSUMERS AND CONSUMER REPRESENTATIVES, CONSISTING OF SIDNEY WOLFE, M.D., DI= RECTOR; HEALTH RESEARCH GROUP; AND PRESIDENT, PUBLIC CITIZEN; ANTHEA SACHS, WESTPORT, CONN.; GLORIA JEAN DAVIS, ALBANY, GA.; JANEY PHIPPS, R.N., GRAY; KY.; KATH- LEEN O'REILLEY; CONSUMER EXPERT, NATIONAL BROADCAST- ING CO.; AND FRANK ADAMO, JOHNSON CREEK, WIS. STATEMENT OF SIDNEY WOLFE, M.D. Dr. WOLFE; Chairman Pepper and members of the subcommittee, thank y,-,u for the opportunity of testifying before this all-too-rare congressional hearing, As you mentioned before, there are a large number of hearings on prescription drugs and nowhere near as many as there should be on over-the-counter drugs. I'm glad to see that you're starting, hopefully, a good precedent. Americans will spend approximately $8 to $10 billion, depending on which set of figures you look at, this year on over-the-counter drugs, but in many ways over-the-counter drugs they buy are not much of an improvement over those available around the turn of the century. A few advances, such as dextro methorphan, for coughs, are overshadowed by the fact that various products which would then have been called snake oils still dominate the over-the- counter drug scene. 32 According to William Gilbertson, Chief of the Food and Drug Ad- ministration's OTC Drug Review, by 1981 only one-third of the OTC drug ingredients reviewed by expert panels called in by the FDA; have been shown to be safe and effective for the intended uses. A more rer Alt analysis of the now 1;819_ OTC_ ingredients which have now been reviewed shows that only 422 or 23.2 percent, have been found safe and effective for the intended uses. Of the 466 top-selling over-the-counter drrig products; almost one- third of them contain ingredients which FDA expert panels have found lack evidence of safety, effectiveness, or both. More than -another third; an additional third; contain ingredients which, like phenylpropanolamine [PPM lack evidence of safety, effectiveness, or both, according to physicians at Public Citizen; a health research group; and many consultant physicians around the country. Thus, over two-thirds of the top-selling 466 over-the-counter drug products in this country contain ingredients which lack evidence of safety, effectiveness, or both. This information is in a book which Will be published this fall by Pantheon titled "Over-the-Counter Pills That Don't Work:" The following 9 examples of top-selling OTC drugs, all in the top 40 drugs in 1981, with annual sales of over $524 million; all contain 1 or more ingredients lacking evidence of safety, effectiveness, or both: Anacin, Listerine, NyQuil, Preparation H, Excedrin, Dristan tablets, Scope mouthwash, Robitussin -cough syrup; and SinuTab: Preparation H is an interesting one when one thinks about snake oil, because one of the ingredients in it, the active ingredients, is called shark liver oil. Another one is called live yeast cell deriva- tive. Neither of these ingredient% as they exist in Preparation H, were found to have evidence of effectiveness by the FDAAdvisory Panel. As a result of this, Americans are wasting at least $3 or $4 billion a year on over-the-counter products which contain ingredients lacking evidence of safety or effectiveness, or which are overpriced. In addition, millions of people are being exposed to unnecessary health hazards of ingredients such as PPA; which is too dangerous for OTC use in diet pills, and hundreds of other ingredients which, in the absence of evidence of effectiveness, provide risks without benefits. Why, given strong laws such as the Federal Food and Drug laws and the Federal Trade Acts, does this wasteful and dangerous state of affairs exist? There are two important forces to protect consumers from dangerous or ineffective drugs in oneinstance and from being defrauded in the marketplace in the other instance. The first is Government regulation by the Food and Drug Ad- ministration over the safety and effectiveness of drug ingredients: The second is FTC action to allow marketplace forces to operate properly by insuring that the power of information, as in advertising, is not converted into an- abuse of-power by false_and misleading promotional campaigns. Both the FDA and the FTC responding to pressure from the drug industry, are doing a decidedly inadequate job of upholding their respective laws; While FDA's over-the-counter drug review can only be described as a major disaster from the consumer viewpoint; it is wellthought of by the OTC drug companies whose trade association, the Propri-

3 33 etarAssociation, is an intervener on the side of the defendant, the Food and Drug Administration, in a lawsuit we have brought, pending in the U.S. court of appeals, which challenges the legality of this drawn out O.T.C. drug review which has failed to take these ingredients, lacking evidence of safety or effectiveness, off the market. The FTC, in the last 2 years, has done even less policing of OTC drug ads than previously. The recent FTC decision a couple weeks ago concerning OTC painkillers must have been pleasing to many OTC drug companies who saw that it was unaccompanied by any demand for corrective advertising and saw it as a retrenchment on the scope or breadth of cases in which ad substantiation would be required: Despite an older FTC decision upheld by the U;S. Court of Ap- peals, Third Circuit, December of last year, which found that Ana- cin's manufacturer had engaged in large scale deception, in ads for Anacin and Arthritis Pain Formula, the misleading ads seen in the next two pages for Anacin appeared the same month; [The material referred to follows:] 84

HEADACHE COLDS/ BODY ACHE NEURALGIA

39 35

A Womise anti Effectivelye. Kept More Mart 137 billion tAitte of ' ANteCINIUM- bsn soldeforx 1930. whin ANACIN was first Introduced. And ANAC1N. used as directed. remains one of thernost imil-tolerated z medkations araibbli, witha history_ oleffkity. bitty (without_ths_riskof tilde effedi_associated with acetamin ophaRnerdoser and reliability that has persisted for 51 years. Todaymilikins o( patients rely_on_ ANACIN tor fag, effertiYe *Victor , headie,/etrrbod_y atne,gental Pain and the ndnor pain of arthritis. For any product. in any pliarrnen- tkal eategorp-that Aib up very health') reTmnr. .

_ Hmorrwrinir 0444.4 36 Dr. WOLFE. The reason I put this in is that it's an ad not over television or in a magazine; but in a_ medical journal; and_the ad nowhere mentions that what's behind the label is aspirin. It mentions that acetominiphin, another_painkiller, can cause toxicity and so forth; which is -certainly -true; but it is no more and no less true than for aspirin. But it fails to tell even doctors, many of whom I suspect are equally unaware as consumers, that the only ingredient in Anacin that is safe and effective for relieving pain is aspirin. The other ingredient, caffeine, lacks evidence of effectiveness. Annual retail sales for the top five product lines of over-the- counter painkillers; the_Tylenols; Anacins; _Boyers; Bufferins; and Excedrins, were about $800 million in 1981, with advertising expenditures amounting to $150 million. Since the only safe and effective painkiller in these or any other over-the-counter drug product is aspirin or acetominiphin, consumers who buy these five product lines would save at least $400 million a year if they bought generic or- house brand aspirin or acetominiphin instead of Anacin; Bayer, Tylenol, Bufferin, or Excedrin. Rather than wasting money on overpriced brand names, some of which also- have ingredients lacking evidence of effectiveness Anacin and Excedrinmore and more people are responding to real competition on the basis of price; not contrived and deceptive differences in quality; and are buying generic or house brand painkillers. Although the other witnesses; including- both medical experts and victims; will discuss in more detail problems which appear to be associated with the use of phenylpropanolamine or PPA, I will briefly review its hazards: The following is taken from our book; "Over- the - Counter Pills That Don't Work." "PPA is now the leading over-the-counter diet aid, accounting for almost $220 million in OTC pill sales:" This is in 1981. With products such as Control, Dexatrim, Dietac, Permatheme, Prolamine, Thin- spans, all containing the drug. No- well - controlled study has shown that PPA is effective as an aid in long-term weight control. It may help you lose weight for- a few days but you gain the pounds back when you stop taking it and it won't help you make the changes in diet and exercise patterns which are needed to keep weight off. The FDA acknowledges that PPA is a hazard to a significant portion of the population, at least 20 percent. People who must avoid PPA include those with any of the following conditions: Hyperten- sion or high blood pressure; heart- disease; diabetes; or thyroid disease. The issue is made more serious by the fact that overweight individuals and hence people even more likely to use PPA; -are more- likely to suffer from all of these disorders discussed earlier, And here is a point which goes beyond any reading of the label. If everyone read the label we would still have a serious problem with PPA. I agree fully with you, Mr. Chairman, when you say that a lot of people, perhaps particularly older people; don't read labels or can't keep 15 or more labels straight if they're using an average of 13 prescription drugs and another 5 or 10 over-the-counter ones; But even if they did; a lot of them would be in trouble. Because it's estimated that as many as 40 percent of diabetics and as many as 30 percent of all people with high blood pressure don't know that they have the disease. Therefore, even if they read the label, they would

41 37 not believe that they are in the group of people who Should avoid the drug. The fact that they are overweight puts them at evena higher risk for diseases such as high blood pressure. As mentioned before, negative reactions occur with theuse of these drugs, even in recommended doses,_ although some of the adverse reactions have been seen with elevated doses. A study on normal medical students in Australia showed that therewas an increased amount of high blood pressure in studentS afterone dose of PPA. This study, unlike most of theones you'll hear -about at the end of today, was not funded by a drug company and I think itcan therefore be more readily believed.- Because even if everyone read the label; many people would not know that they shouldn't take the drug, millions of PeoPleare Un- aware that they have a disease which may seriously be impaired by taking PPA,-namely, -high blood pressure or diabetes; PPA is too dangerous and has an effectiveness which is too Mar- ginal or too short-lasting to be allowed for saleover the counter. Someday we will look back on the PPA &Cade, 1975 through 1985; and wonder who-in the FDA was reckless enough to allow its use, or Who in the FTC was reckless enough to allow its misleading ads such as one which ran for Maximum Strength Dietac, pushing, "A new diet aid without caffeine- or other stimulants." Obviously, Something that is in the same family as amphetamines and which has been shown in a number of cases to causean increase in blood pressure and a number of other kinds of excitement of the central nervous system, is, in fact, a stimulant The clearest statement about the faddish buSineSS of diet pim comes from a drug company executive who said that in the sixties there were rainbow pills or thyroid stimulators. Then therewere amphetamines followed by candy, CIVIC or carboxymethylcellu= lose--benzocaine, and now PPA, which cannot last; either. You don't need any of them. If you have the willpower to cut downon your eating and to exercise; you lose weight. The drug company ex= ecutive, of course, fails to mention that during these fads, thereare many; many victims such as the people you will hear from in a couple of minutes. I'd just like to close by saying, as has been said by people both to the right of you and to the left of you, that this is not meant to be An open-and-shut attack on over-the-counter drugs; In our book and in statements we have made over the 12 years we've been around, there are some very useful over-the-counter drug products. They are mainly single-ingredient products such as the painkillers, the acetaminophen and aspirin, the drug for treating coughs tffectiv- iy, if you really need a cough suppressant; if you can't sleep at night and you aren't bringing up anything, dextromethorphan, and so on. But most of the 300,000 over-the-counter drugs on the marketare either overpriced or contain ingredients lacking evidence Of Safety and effectiveness and, as I mentioned before; are causing Ameri- cans to waste $3 billion or $4 billion a year, The idea of self-treatment is a very important one, particularly in older people who are loaded up with too many drugs; both over the- counter and prescription. Senreatment is different from Self=

42 38 medication becauSe Many kinds ofself-treatment don't necessarily involve medication. It's been saidby eXPerts from the Nationalin- stitutes of Aging that elderlypeople_ really shouldn't betaking over-the-counter lakatives, one of thecategories of drugs that they most frequently take. Instead; they could use dietary _meanssuch as having larger higher fiber in their diet, Thisis_just one amounts of liquids and But example _where self-treatmentdoesn't involve *f-medication: sometimes_ it has to involveSennedication. There are some safe and effective overcthe=counterdrugs around. If Americans focused on them insteadof the much larger numberthat have ingredients that aren't effectiVe; would all be better off: Thank you very much. I'd beglad to try and answer any questions you have. Mr. PEPPER. Well, thank you verymuch; Dr; Wolfe, fok your ex= cellent statement. Our next witness is Mrs.Anthea Sachs of Westport; Conn;We are pleased to hearfroM you, Ms. Sachs. STATEMENT OF ANTHEA SACHS Ms. SACHS. In August1980, I was anxious to lose 10pounds before my son's wedding, andseeing_ a large display of diet pills by the checkout counter at the drugstore; I asked the manager ifthey worked; it seems too good to betrue. He Said, "A lot of my customers seem to getgood results With Dexatrim."After reading the warnings on the back and seeingI had none of the illnesses, such as high blOod pressure,diabetes; or glaucoma, or any ofthe others listed, I thought it would be safeand bought the extra strenghsize. f was on no other medicationand at 61; was in excellenthealth. I took one_pill a day; asdireated, for nearly 3 months; went on a strict diet; and lost 10 pounds.On November 17, 1980, -I had a cerebral hemmorhage and nearlydied. I spent 18 idays in NewYork Hospital. Since then; my memoryand my hearing have deteriorat- ed and my coordination is very pm..Worst of all, I have trouble with words, often saying hotwhen I mean cold, _or housewhen I mean hotel. Sometimeswhole Sentences come outthe wrong way. However; I feel I am one of thelucky ones as I can still function fairly well on my own. Unfortunately; as long as theSepills are readily available, no amount of warnings will people from taking what seemslike an easy way tolose weight; I have friendswho,_ in spite of what happened to me; are stilltaking Dexrim; confident itwon't happen to them. In spite of all mywarnings about them. These diet pills are dangerousand should be taken offthe market Mr. PEPPER. Well, thank you verymuch, Ms. Sachs. Next is Mrs. Gloria Jean Davisof Albany, Ga. Mrs: Davis; speak right into themicrophone; please, ma'am. STATEMENT OF GLORIA JEANDAVIS Mrs. DAVIS. My name is_GloriaDavis. I am a resident ofAlbany, Ga. I am .32 years of age. Ihave four children. 3 amdivorced from my husband. 39 Lillie Thornton Zackery will read my statement. Ms. ZACKERY [reading]: In May or 1978 I decided to try and lose some weight. _I went to a local store and purchased some over-the-counter diet pills to assist me in losing weight, Lwent back home, read the directions that came with the diet pills called _appedrine and took some pills that day pursuant, to the directions. Shortly after taking the pills I developed a severe headache. My family rushed me to z local hospital where I passed out. The doctors diagnosed my condition as a stroke. The doctor asked my mother, whom I lived with at the time, whether or not i had taken any medicine. She said, "No, except for the diet pills." After seeing the diet pills that were taken to the doctor's, upon their request, the doctor said that they were certain that the diet pills caused my blood pressure to go up extremely high, thereby causing the stroke. Prior to taking the diet was in excellent health and was taking no medicine of any kind, whether pres_criptive or non-prescriptive. I have never had high blood pressure_in my_life_prior to the stroke. After the stroke I was in the intensive care unit at the hospital for 2 months and then in a wheelchair for the following 6 months. Although it has been approximately 5 years since the stroke; I still have little use of my right arm and leg. The doctors say my condition is permanent. Before the stroke I was employed but now I cannot work due to my physical con- dinon caused by the stroke. I did sue the company which produces this diet drug, and won my case. However, others will not be as fortunate as I was. Mr. PEPPER. Thank you very much; Ms; Davis. We are sorry that you have experienced that tragedy. Next is Mrs. Janey Phipps, a registered nurse of Gray, Ky. STATEMENT OF JANEY PHIPPS Ms. PHIPPS. Thank you, Mr. Chairman. I am a registered nurse and I work in a coronary care, intensive care, unit; and I've worked in this unit for 4 years. Two and a half years ago, after the birth of my second child, I wanted to lose some weight. Subsequently, -I began to take an over- the-counter appetite suppressant known as- Dietac: Before taking this preparation I read the label of ingredients; noting that this particular brand contained- a drug known as phenylpropanolamine hydrochloride, known as PPA. Dietac, the particular brand that _I took, contains 75 milligrams of the PPA per timed release capsule. I also noted the warning on the package cautioning people with heart disease; hypertension, diabetes; and thyroid disease not to take the preparation. I considered myself a healthy person; having none of the above-mentioned afflictions and therefore began to take the drug, as directed, one capsule daily; On the fourth day of my diet regimen I began to feel unusually and intensely fatigued. I decided to lie down and relax. In doing so I felt so fatigued that I actually ached all over. I became aware of an odd feeling of slow pounding in the center of my chest and soon realized the general body aches coincided with each slow pulsation. I soon realized that the pulsation I was experiencing was; in actuality, my heart rate. I counted my radial pulse, that's the one that one feels in the wrist; and itwas 40, for I full minute: I had my hushand take my pulse and he also counted 40 beats per minute. I became very concerned about this rate and counted my heartbeat with my stethoscope, and it was still 40.1 then realized that something terrible was happening to me. I went to the hospital and was admitted to the same coronary care/intensive care unit where I worked. I was placed on the cardiac monitor that showed my

44 40 heart was only beating 36 to 40 times per minute.This condition is known as sinus bradycardia. My blood pressure was extremelyelevated, being 200 over 120- At that point I realized two distinctdangerous possibilities. First of all, that the electrical conduction system in myheart could become further arrhythmic and I could die. Second,I could have a stroke: I remember haVing thoughts of denial anddisbelief that even this could happen to me. My physician; Dr. Glen Baker, wascalled to see me. He prescribed intravenous atropine sulfate to increase myheart rate. After receiving the atropine sulfate; myheart rhythm changed from the aforementioned sinus bradycardia to ajunctional rhythm. This means the electrical impulse thatnormally begins in the sinus or §inciatrial node in the heart hadbeen taken over by the atrial ventricular node in the heart. Thisheart rhythm is not a normal conduction pathWay. - I remained in this heart rhythm for severalminutes and my blood pressure remained elevated. I was fullyalert and aware of everything that was happening to me. After thejunctional rhythm, my heart rate increasedand converted to sinus tachycardia, a normal conduction pathway; except theheart rate is greater than 100 beats per minute. Gradually, myheart rate slowed to a normal sinus rhythm- and my blood _pressurereturned to normal. The queS= tion was what caused these problems. I told my physician the only drug I wastaking at the -time was the Dietac preparation. He-immediately suspected the PPA caused my blood pressure toelevate: But why did I have a Slow pulse? Normally; the PPA would cause a fast pulse ortachycardia; I stayed in the hospital for 3 days,undergoing various tests, all of which were normal. I also saw acardiologist. The slow heartbeat, my physician explained, was causedfrom excessive pressure on my carotid arteriesduring the hypertensive episode. Thecarotid arteries, located in the neck; are very pressuresensitive, and when stimulated cause a slowing of the heartbeat.This is due- to the stimulation Of the parasympathetic nervous system, adivision of the autonomic nervous system; I assumed that because a drug issold over the counter and not by a prescriPtion, that a drug is safe.How many other people, par= titularly the elderly, also believe thisassumption? The older individual, who statistically stands to havehidden heart disease and hypertensidn are at great risk when takingover-the-counter preparation§ containing the PPA; If somethinglike this can happen to a healthy; youngindividual like myself, it can happen to anyone; Mn PEPPER. Thank you very much,Ms. Phipps; You've heard the signals here and you see the signsindiCating there is a vote on the floor. And we will have to take atemporary recess until we can run over and Vote. Thenwe'll be right back; [Brief recess.' Mr. PEPPER; The committee will cometo order, please; Our next witness Wfil be Mrs.Kathleen 0Teilly, consumer expert of the NationalBroadcasting CO., and an experienced lawyer in this field. Mirs. O'Reilly, vie arepleased to have you here today. 41 STATEMENT OF KATHLEEN O'REILLY Mrs. O'REILLY. Thank you, Mr. Chairman. Last October 27the NBC "Today Show" aired a segmenton PPA and diet pills, and a copy of the transcript of that segment will be provided for the record, but with the hope that we don't haveany mechanical problems, we will show that excerpt now. Mr. PEPPER. Is this it Mrs. O'REILLY. Yes. MT. PEPPER. Oh; good: [Videotape shown.] ANNOUNCER. The drug industry sells 10 billion diet pills a- -year, but there'sa growing controversy over whether these nonprescription diet pile work and whether they re safe With us is consumer expert Kathleen O'Reilly. Mrs: O'REILLY. The main active ingredient in diet pills is phenopropanolamine PPA for short Its PPA in small doses which generally is takenas a decongestant But according to consumer groups,_ a much higher dose of PPA in dietpills is neither effective, nor safe, especially for consumers with high bloodpressure or hypertension, the very consumers who are often overweight. This diet pills box says to use up to 3 month% The diet pill ads oftenspeak of danger for a longer period, 27 _weeks; 2b weeks-, 36 weeks. Theaverage weight loss, according_to_Science in the Public Interest is only in the first few weeks,far a total of about fourpounds: VOICE: Studies conducted by Thompson Medical itslf have shown that theexpect- ed weight loss can be anywhere from a third to a half a pounda week. Mrs. O'REILLY. What about the safety of PPA? It's ill-advised for_people_with high blood pressure, heart disease, diabetes, thyroid, kidneyor other disease% and has been linked to stroke% cerebral hemmorhages, and other cardiovascular disorders. Since 40 percent of those who am overweight do suffer from hypertension andre- lated medical probleras,_andeven_more are borderline the Center for Sciencein the Public Interest_has warning language to be included in allas since overweight consumers are most vulnerable to PPA's adverse potential. Industry claims that warnings on the box are sufficient, and that the Food and Drug Administration has approved PPA. VOICE. They have found that with hundreds of thousands of doses being takenon a daily basis that there is a very small, negligible, incidence of adverse reactions and have, therefore, found that the product is safe and effective. MrS. O'REILLY. Is that the FDA's position? VOICE. Not really, no. As a m_atter of fact, the Food and Drug Administration has not put forth its policy with regard to the safety and effectiveness of these drugs to date. What we did, was to publish the report of an expert advisory panel. We have expressed some concern about the panel's recommendations for dosages of phenylpropanolamine and as a matter of fact_ we dissented from the panel recommendations to increase the dose that's already-in use out in the marketplace. Mrs. O'REILLY. Frank CrDonnell of Milwaukee had no medical histou suggesting a potential problem with PPA and says he took the diet pills as directed. But yet he suffered a stroke. Mi. O'DONNELL. Well, I had a numbness in the back of my arm and numbness in my face, and those are the permanent_result of the stroke. Mrs. O'REILLY. Cut down on calories, increase exercise; common sense: That's the recommended way to Lose weightsafeb% Does that include diet pills? The _Food and Drug Administration him recently expressedconcern about -the safety of PPA and will; within a year, decide whether or not these drugs should be banned or otherwise restricted: Two years ago the Federal Trade Commission staff recommended legal action takenagainst the manufacturers of these proaucts, but still no formal action has been Dr. Thaddeus Krout, a medical expert in the field of PPA: Dr. KROUT. The tragedy is that this relatively useful agent decongestion is now abused by the false advertising which has been Iroughtforth by the companies that want to make a great deal of money_ out of this whole situation, Mrs. O'REILLY. Whether or not the government takes action on this issue of PPM remains to be seen in the next few months: We will be watching it In the meantime people are becoming very suspicious of other over-the-counter drugs. We're going to be talking about the tampering problem. [End of videotape excerpt.] Mrs O'REHAN. I would now like to highlight for you the major objectionS to that piece that were raised by Thompson Medical, and describe the legal and scientific basis which did support this segment. Fir St, Thompson Medical objected to the language that said; "It's PPA in small doses that's generally safe as a decongestant, but according to consumer groups, the much higher dose of PPA in diet pills is neither Safe nor effective." It was Thompson Medical's con, tention that the facts are just the opposite. The dosage permitted by the Food and Drug Administration in decongeStantS is 150 milligrams per day, While the permissible dosage inover-the-counter appetite control pills is only 75 milligrams per day. Our response is that the higher dosage for decongestantS, cough remedies, and the like, reflects the fact that these cold remedies are typically taken for only a fvii days at a time; whereas dietpills are taken for weeks and months at a time and thushave scientifically significant, cumulative effects. And as we have heard today, those cumulative effects are particularly relevant for the elderly, who are taking many more medications, both over the counter, and prescription, than the population as a whole. It is also a reflectiOn that the higher long-term concentration of diet pills has raised the safety questions at the Food and Drug Ad: ministration. Although the FDA advisory panel had recommended raising the permissible dosage in appetite control pills; the FDA specifically rejected that recommendation, and we will submit to you the Federal Register announcement on that And they also had expressed concern that the diet pill package§ do not universally include language alerting consumers to the problem of taking diet pills in addition to taking other products that contain PPA, which is an additional medical risk. Thompson Medical also objected to that statement in the script that said the consumer groupS were questioning the efficacy and the safety of PPA and diet pills. It was Thompson's contentionthat all evidence shows that_ PPA in diet pills is effective and Safe. We pointed out to them the number of scientific studies that have been printed in the Federal Register; including the summary, pointing out safety problems involved with PPA in diet pills.We also pointed out that if there were no Safety questions, why dothe FDA regulations specifically state that all markeddrug products containing PPA bear or contain a statement warning against use by individuals with high blood pressure, heart disease, diabetes, or thyroid disease. We also pointed out that in the leading case of Porter v. Dietsch the seventh circuit upheld a Federal Trade Commissionorder requiring a manufActurer of diet pills containing PPA toinclude such a health warning: Indeed, most of the diet pillpackageS do contain such a warning, and Dr. Ekien, who was interviewed on camera, Who is the head of the proprietary association;stated that, on camera, !Vs._manufacturers are in the process of including such a warning." Dr. Ekien did not state orhint that such a warning would be unreasonable. 4 43 Thompson Medical also objected to that part of our segment which stated that the diet pill box says, "Use up to 3 months, ' but the diet pill ads often speak of dangerous longer periods. Thomp- son's contention was that there is no evidence that longer use is either dangerous or unsafe. Both the Federal Trade Commission spokesperson, Amanda Pe- terson, and the FDA spokesperson; Dr: Halperin; expressed concern on camera about this very issue. Under FDA procedure; the burden of proof is on the drug manufacturer to demonstrate the safety and efficacy of a drug; and as Dr: Halperin explained, FDA does not conduct its own scientific studies. It evaluates the studies which are initiated and paid for by industry. The diet pill industry-had not submitted studies involving more than the 12-week limit. With this as a background; it is important to note that under the Food, Drug, and Cosmetic Act, drugs are only legally safe when used in dosage manner, or with a frequency or duration described or recommended in the labeling. The duration prescribed and recommended on the labeling of diet pills_is -Up to 3 months." Thus, usage beyond that period cannot legally be characterized as safe and caselaw supports that principle; the leading case being, The Pharmaceutical Manufacturers Association v. Richardson. Even Dr: Ekien said that the 12-week period is not meaningless, and he expressed manufacturer concern over the abuse of these drugs, and in no way attempted to refute the wisdom of that duration limit; explaining that the pills were to be used temporarly as an adjunct to an overall program of weight control. As to the question of efficacy, Thompson Medical contends that on the basis of 14 clinical studies, the average weight loss on PPA is over 1 pound per week for a considerably longer period -of time than described in our segment. We pointed out that scientific studies show that people lose weight even with a placebo and these double blind studies :re routinely _used to evaluate real weight loss: Indeed, the FDA pa1 had specifically rejected a Thompson Medi- cal study because ivas not a double blind study, and had recommended double blind studies as the protocol to be used: Under this commonly accepted scientific procedure, the placebo weight loss subtracted from the product-associated weight loss is used to arrive at what is arguably called "the real weight loss attributable to the tested product." That is the reason the Thompson studies, which do not discount for the placebo effect, are different in their results from the studies which use the scientifically-accepted method of double blind. Thompson Medical also contended that Bruce Silverglade of the Center for Science in the_Public InteresVs statement that studies conducted by Thompson Medical Co. itself have shown that the expected weight loss can be anywhere from one-third to one-half pound per week; were_inaccurate We have provided these scientific studies on which Mr. Silverglade's comments were made. Also, Thompson Medical objected to that part of the script that said PPA has been linked to strokes; cerebral hemmorhages; and other cardiovascular disorders. This is significant in that Thomp- son contends that no causal relationship has ever been established.

d 44 The script language is the Verbatim cautionary languageinclud- ed on the diet pill box labels. But it is not yet contained inthe ads, despite the Porter-Dietsch decision; and that is the basis of thepetit tion by the Center for Science in the PubliQ Interest.It's important to understand the terminology "causalrelationship" is not the FDA legal standard. For example; the recent baiis regarding Ora-Flexand starch bloekers Were based on the traditional standard of linked orassoci- atedWith health _problems; and the Center forScience in the Public Interest had submitted for the record a variety of theexamples of that link. Finally, the whole notion of whether or not there is a suggestion that industry is_claiming that the Food and DrugAdministration has approved PPA. In the script you-saw that D_ r.Ekien from the proprietary association made that comment: It was )mpson Me- dical's contention that that had been taken out of col, that he was only talking abOut theU.S. FDA panel. I will submit the extensive, word for word;interview with Dr. Ekien and you will see that he was specifically talkingabout the FDA, apart from the U.S. Panel. I read, for example, myquestion to hith was "Has the FDA itself found PPA to besafe and effective for over-the-counter use?" His response: The FDA has issued a tentative proposal with respect toPPA which they have not dissented from the panel's recommendation. Thatis tantamount to their saying at this point; giving an okay to this molecule. I think most important of all is the fact that inJune of last year the National Advertising Division of the Council ofBetter Business Bureaus; which is the self-regulatory mechanism of theadvertising industry, reported that Smith, Klein, Beckman Corp, .manufacturers of Dietac Maximum Strengthdiet aid capsules, had withdrawn its advertising clainis pursuant to a NationalAdvertising Division challenge. In that report, MAD states; and I quoiJ,"Additionally, the Na- tional Advertising Division felt that reference to a quote;''U.S : -government advisory review panel', end of quote;implied official en- dorsements by the government itself." Not only isthis industry watchdog conclusion consistent with our script narrative;Dr: Ekien himself was explicit in that respect. Finally, the issue of whether or not the fact thatthe FDA has recently expressed concern about the safety of PPAand will, withinyear, according to Dr. Halperin; andthat quote came from last September 20, decide Whether or not thesedrugs should be banned or otherWiSe restricted. It was Thompson'scontention that thiS falsely implies that PPA is dangerous and thatFDA will either ban or_restrict its Use. What the FDA hag actually done, however, is merely tohave included this drug under its continuing reviewof all over-the-counter products. We pointed out to them the specific concernsraised in the Federal RegiSter by the FDA went waybeyond the aspects of continuing review and supplied those studies aswell._ So; I hope that thiS may be instructivein responding to the major SubStantive contentions thatThompson Medical had raised on the basis of this segment.

9 45 Thank you._ Mr. PEPPER. Thank yot.. 'Try much, Mrs. O'Reilly. Did you want to make a statement? Mr. ADAMO. Yes. Mr. PEPPER. Well, could you wait and let us take it in a little more orderly way? We have this panel here and it's customary, now; to allow questioning of the panel by members of our commit - tee. Oh, I'm sorry. __I understand from the staff that you should be heard; sir. Go right ahead. You were one of those who were supposed to be on the panel. I'm sorry. We just didn't have room for you. Mr. ADAMO. My name is Frank Adamo. Mr. PEPPER. Mr. Adamo, we are pleased to have you: Mr. ADAMO. Thank you very much. Mr. PEPPER. We're glad to hear your statement. Mr. ADAMO. I'm pleased to be here; STATEMENT OF FRANK ADAMO Mr. ADAMO. I do recognize that the hearing on the safety of PPA usage is being held through the Select Committee on Aging, and is concentrating primarily on those PPA-related cases involving older people. However, I believe that the problems caused by PPA usage cut across all age groups and to disregard an episode based on my age would-be- doing a disservice in your efforts to determine whether or not PPA is, indeed, safe and effective, as advertised. In October 1980 I began using Dietac diet medication. I chose Dietac because it is manufactured by the same company that produced a well-known cold medication, and the advertisements I heard convinced me not only of the safety of the product but of th effectiveness as well: I followed the label directions, taking one time release capsule a day, each containing 75 milligrams of PPA, and 200 milligrams of caffeine. I was on no other medication at the time. -- On January 19, 1981, while at work, I suffered a stroke. Hospital- ization and a battery of tests revealed an area of damage to the blood vessels in the right side of my brain. Because I was healthy and had no history of medical problems, my doctor was puzzled as to the cause. I was 28 at the time. My doctor put me on blood thinning medication in an attempt to prevent any further episodes. On October 19; 1981; I heard a report on the radio linking PPA usage with a variety of medical problems, including high blood pressure, personality changes, and strokes. I got in touch with the Center for Science in the Public Interest; who had released that report. The more information I received, the more convinced I became that m_y stroke was caused by PPA ingestion. I related all the information I could obtain to my doctor._ Although he would not commit himself to a direct link between PPA and my stroke, after reviewing the information he felt confident enough in the possibility of a link to take me off blood thinning medication. I have not experienced any further problems since my stroke, when I stopped taking Dietac and avoided any products rrtaining PPA.

27-436 0 - 84 - 4 5i) 46 When I consider all of the possible effects I could have suffered from having a stroke, I feel extremely fortunate that I don't have any of the obvious physical problems or disabilities resulting from my episode. But there are those who have suffered even more serious and permanent results from PPA ingestion, and I can't help but wonder how many more people have suffered various medical problems and are unaware that the cause was PPA ingestion. What happened to me and to the many other victims should never have occurred. Despite the advertisements to the contrary, I feel that PPA has_been shown to be_a_ very unsafe and dangerous drug and further, I believe that the FDA has an obligation to protect the safety of the American public, particularly any potential future victims, by prohibiting the use of PPA in any and all over- the-counter medications. Thank you very much. Mr. PEPPER. Well, thank you very much. Ms. Ferraro, would you care to make any statement before we start questioning the witnesses? Ms. FERRARO. No, Mr. Chairman. I'm just delighted that you're having these hearings. I have participated with you in the joint hearings that we had with the Senate and I look forward to picking up_ on the testimony of the witnesses. Mr. PEPPER. Thank you very much. I'm very sorry that I've got to go to another meeting, and I'll ask Ms. Oakar if she'll preside: And now you will proceed to question the panel. I want to thank each one of the panel this morning for your excellent statements and for your coming here to help us in this in quirt' We're just trying to ascertain the truth for the protection of the elderly people of this country. And I want to thank all the other members of the excellent_program that we have here today, and I'm sorry that I'm not going to be-able to hear you; but I hope toile able to read the record. Maybe I can get back a while later. Ms. Oakar. Ms. OAKAR. Mr. Chairman, I want to submit for the record correspondence between Congressman James Florio and the FTC regarding advertisements for diet pills. I think that this is especially important in light of the fact that on a particular box of diet pills the language used to lure people to buy the product is three-fourths of an inch high compared with the less than one-sixteenth of an inch print used to describe the warning and caution caption. This lures the consumer to these unsafe products. [The material submitted by Representative Oakar follows:] 47

of 1;rp:rstniatitits ::::r1::n:111:orCtrltnfttl. Clersrenallon antCOUTISM e tor Commit:ft on Cnttir ant Comentret trnatliington. 23';I:, February 24, 19E2

Bon,:rar.e C. Miller, 731 Cnc.tt-met. 7raf, 440 ;Nenue, V. V. tor., O.C. 2Ct,E0

c:afrs tap.a..!dinc the safety and effectivenett_of iCrOC) diet pins containing phenylononanolamine .anticc]ar attention fn recent years.

l_E..;";, the F7c,_:4-cegni:fnc_pro'rlems with nannfacturprs' POdUCtE, OrECrEe Dr0:11.):ErS to cease_and_oesist -nnp,:veafvertisinc claims and to include a health warning :t has been brought to the Subcoc, *,ec'F c.:tr7-icn fAat r r.rt and suhztantial violations of 1S-;7 :7:fen .ave vccurzed, th- prcr.ptinc_staff of the Bureau of 7:ctenton ts cect77.7end :ate_254 that_civtl penalties arsessen' agafnst certain f.rms. En.-ever; no an:on nas t,,ken on these recortztenf.ations.

w:+uld the status of _any review-of-diet pill a6venttsf.ng, the dfspc5ition of the ttaff recommeneEtionsto civil.penalties, and the FTC's current policy with regard to the ieculation of diet pill advertiting.

Your attention to these matters is appreciated.

Sinc

J. Florio; Chairman Sukcommittet.On _ Commerce, Transportation and Tourism .7.7F:rfs

5. 48

FEDZRAL TlADE COMM:SSION NASHINGTOA. D C.70f80 Bliti-AD OF CO:NSUNtEF. rhOFECTION

Tvi? 2 5 itit

TSe ronoraole James J. Florio Csairman. Sobcommirtee_on Commerce-, __ Transportation and Tourism Committee_ on Energy_and.Commerce house of_ Representatives Washington; D.C. 20515

Dear Mr; Florio:

Chairman MiIlet has requested-that l_answer.your February 24; 2922, letter concerning advertising for over-the-counter diet cads containing phenylpropanolamine. hydrochloride ( ?FA). 1 unserstasd that you are concerned that_current advertisinc for diet aids may oe_deceptive and contrary to the holding of our_recent_Porter_and_Dietsch_cese-90 F.T,C. 770_(1977), modifiec, 605 F;26 294 (7th Cit;_1579);_cert.__denied. U.S. 950 (1980); aMehOMehtt to order; 95 F.T.C. 806 (2980).

In Porter and Dietsch respondents -ware ordered to_disclose in future advertising for a PPA-containing. diet aid,__ X-11i that the product should not_be used i;44thout medical supervision by persons with hypertension, heart oiseese, ciabetes or thyroid, disease; and to disclose that successful use of the product requires dieting. At the same time the advertisers of.X711_were ordered to stop making unsubstantiated exaggerated weight_loss claims. The FTC reasoned-that the clinical evioenCe_reIied_on by respondents that showed no mere than a fraction of.a pound of weight loss per-week on the average was insufficient to substantiate a-claim that consumers experience dramatic weight loss as a result of using X-II;

In your letter you-advise Chairman Miller, It has_been brought to the Subcommittee's attention that subsequent and substantial violations of the 1977 oroet Lave - occurred i thus prompting staff of the Bureau of Consumer Protection_to_recommend that civil penalties be appropriately assessed against_certain_ firms." The FTC Act permits us to seek civil- penalties or_other redress for violation of the FTC Act-in two situations:, (1) where -the named respondents have violated a finaladjudicatedor consent order against them, and (2) where on y party has knowingly violated a final order resulting from a fully litigated Commission adjudication. 49

To our knowledge, the named respondents in Porter and Dietsch have been in substantial compliance with the order against them. With respect to other parties, who were not named in tne Per-t-e-rand case, they cannot be in violation of the order until they know the acts or practices that are prohibited by it. The Commission practice is to adopt a formal synopsis of the case and serve it, along with a' copy of the FTC opinion and order, on tne pertinent industry members. Thereafter, any industry member woo continues to enoage in the proscribed acts or practices is in violation of the FTC Act and may be sued for civil penalties or other redress.

At the time thatT became Bureau Director in October, 1981, a staff recommendation was pending that tne FTC adopt and serve a synopsis based on the Porter and-Di-etsch case. After reorganizing the Bureau and dealing with several budget and reauthorization matters; I made this ratter one of my priorities. I am considering in conjunction with certain diet aid advertising whether to serve a svnocsis of Porter and Dietsch. I anticipate tnat in E short time I will reach a final decision on ..ne;roer this synopsis is necessary; and if so what it should include.

I hope this addresses your concerns and those of your Co=ittee:

Sincerely yours;

Timothy J. Kuris Director 50

. . .

iu,:e.poust oflArpttsrntatibts kubcommitter on Com:null. transpottation. anb ttuttsm orIbl Commoirt on Craw anbC4171171M1 faatbington. D.C. 20515 REcchem August 9, 1982 US] Tne honcrale Janes C. Miller. III ChaIman, Federal Trade Commission BOOn44C '44-Rt.t5c/ 6th Fennsylvania Avenue, N. W. Washington, D, C. 20580 Dear Chairman Miller:

This is in further_reference_to_our correspondence-concerning over-the-counter diet pills containinc _p'nenylpropanblamine, In my letter of February 24, 1982, 1 reouested a report on the vtatus of the Com,nission's rev:ew of diet pill aovertising._By_ laz;-er_Of_::arCh 25;_19S2, the :,:rector -c` the Bureau of Consumer rotection, Mr. Timothy J. Murls. uctes_my ccncern_that current w.iverzain::: for diet pills may be contrary to_the_hOlding_in_the It. ter and D:etsch case. Mr. Muris stated that he had made this 1r5A-6_aThoriLy matter and expected-to reach ac early decision C n whether to proceed_under_the_Commission's Section 5(m)111(B) authority, i understand that other enforcement options might also be available.

With the passace of -oval four months -since Mr. Muris' letter t9 furtoet_indication_of activity, I. am writing_again- tc Inquire as tc the status of your action and the reas'on_for_deliy; snze-t-nis matter involves allegations of serious public health hazards, including strokes experienced by those using diet pills, the possibility -of ongoing flagrant violations of the laws-administered by the Commission is of grave_concern_to_me. In_thiS recard, press reports have been called to ms attention which sug,est that overall,-the enforcement activity of the Commission in_recent_mdriths_has_been drastically reduced-While I would not necessarily credit these reports without further substantiation, I am concerned that the diet pill matter may reflect_some even more fundamental underlying administrative difficulty of which the Congress has not been apprised.

I look forward to hearing from you on this matter

Florio, Chairman bcommittee on - erce, transportation and Tourism JJF:pjs

100 51

Mi..... on. ougc of 3,cpreocntatibt5 Comma on !now anb Comtneur

SUBCOMMITTEE ON COMMERCE, TRANSPORTATION, AND TOURISM

Viatsbington, )11.C.20515 April 14, 1983

The Honorable James C. Miller, III Chairman Federal Trade Commission 6th and Pennsylvania_Ave., N.W. Washington, D. C. 20580 Dear Chairman Miller:

I have received a letter of April 12, 1983, from Timothy Muris of your staff, enclosing a copy of the synopsis of the £orter & Dietsch decision.

As you know from our-prior-correspondence, I have had -a- long- standing concern regarding this matter. I remain troubled by the extended time it took for the FTC staff to bring this matter to the Commission for decision;

Additionally. the synopsis raises a number of new questions in my mind. First, while Mr. Muris' letter states that tne synopsis has been releavd, it does not say that it has been served. Please advise me when such further action may be contemplated. Second, it appears to me that there may be a number of problems relating to the promotion of over-the-counter diet aids containing PPA which are not addressed by the synopsis. While the Commission may have decided -not to_pursue these matters under its section 5(m)(I) (B) aUthority, I trust that the appropriateness_of other enforcement initiatives_will_be_considered_prompllyGiven the indications or the widespread advertising of diet aids containing PPA and the potential adverse effects on consumers, further delay is unwarranted and could raise serious questions about the commitment of the Commission to protection of the consuming public.

I appreciate your keeping me advised on the progress of this matter.

James _J o_io,_Chairman Su mittee on Commerce, T portation and Tourism JJF:pjw 52

Federal Trade Commission Washington,D.C. 26580

FOR IMMEDIATE RELEASE: AppiI 1;1983

FTC OUTLINES_UNACCEPTABLE_ADVERTISING_ FOR SOME WEIGHT-CONTROL PRODUCTS; PLANS

The Federal Trade Commission today described what it considers to be deceptive advertising for some weight control products and plans. The Commission's goal -is to ensure that marketers of weight control products and plans -are aware -of the provisions of a 1977 FTC order against Porter & Dietsch Inc. Thai company's product contains the appetite supprestent phenylpropanolamine hydrochloride. The FTC notice -- called a synopsis -- outlines key aspects of the Commission's Porter & Dietsch decision. It reminds the industry that an advertiser_must have a reasonable basis for claiming a product or_plan_will bring about weight loss. ,Also, a Claim of scientific support_for a_statement about such approduct is deceptive if the evidence is_not_competent or does not fully support the Statement at the time it is made. r. Along-with these provitions_; the_Commission_pointed out it is unlawful to claim that a weight control_product_contains a unique ingredient, unless that ingredient is absent_from other available weight control products. And -the Commission_ also cautioned against the use of testimonials misrepresenting_ directly or indirectly that any particular experience with a weight control product or plan reflects a typical experience.

Copies of the synopsis are available from the FTC's- Public Reference Branch, Room 130, 6th Street-and Pennsylvania Avenue N.W., Washington, D.C. 20580; 202-523-3598: TTY202-523-3638. air

MEDIA CONTACT: Janet Bassi_Office of Public Affairs, 202-523-1848

STAFF CONTACT: Susan Elliott, Bureau of Consumer Protection, 202-724-1499

(Docket NO. 9047)

[Porter]

5 7 SYNOPSIS_OF_FEDEWAL TRADE COMMISSION_ DETERMINATIONS CONCERNING PROMOTION OF PRODUCTS ANDPLANS FOR WEIGHT CONTROL-

Porter & Die-tsch Inc. Docket 9047

ThiS Synopsis has been_prepared_for_purposesof 15 U.S.C. 545(M)(11(B), a law which provides_forCivil penalties for certain violations of the- Federal Trade Commission Act, The Federal Trade_Commission _has determinedthat the following_acts or practices are deceptive -and are unlawfulunder Section 5ta)(1) of the FTC Act; 15 U.S.C; S45(a)(1).

A. It_is_deceptive to represent, directly_or_by_implication, that use of an appetite suppressant,and/or methyleellulose; enables_a person to lose body weightor fat without dieting or restricting his or het accustomedcaloric intake.

B. _Itis doeeptive to represent' directlyor by implidation, that a weight control productcontains_a unique ingredient or component, unless the ingredientor_component is not present in other available weight control products;

C; It is deceptive to_represent, bymeans of testimonials,_ directly or by implication; thatany particular expertence with weightcontrol_product or plan reflects the a typical or ordinary .. experience of users of the product orplan, unless the representation is true;

D. It is deceptive to represent, directlyor by implication:

_ 1._ that,use of a weight controlproduct_orplan will_reSUlt in -loss of body Weight or fat, withoutpossessing and relying upon a reasonable basis for the representationat the time it is disseminated:,

2. that scientific evidence supports a statement about a weight control product or plan, without possessinuand relying upon competent scientific evidence that fully supports the statement at the time the representation is disseminated;

Approved:

Resolution: Approved _ _ _ in File 802 3132 Marketers Of Weight Control Products and Plans

As used here, "weight control" includes_the_reductionor elimination of fat with or_without_weight_loss;__ ThiL synopsis is based on the_COmmissioes Porter & Dietsch decision. The decision was approved; with a feW etitingei, by a federal appeals court._ _A further appeal to the U;S. Supreme Court was turned -down: The legal- citation -for the case is 90 F.T.C. 770 (1977); modified,_605 F;2d 294 t?th Cir. 1979), oert;_denied,_445 U.S. 950 (1980), amen-drne-n-t-st-o- order; 95 F;T:C; 806 (1980).

5 s 54 Ms. OAKAR. '!'his is a problem that affectsthe elderly as well as younger people. It cuts across agegroups, although the elderly with all their problems of older ao have moretendencies toward high blood pressure, et cetera. -I want tosubmit a computer printout which indicates that over 1,000 peoplehave reported adverse reactions to PPA recently, and a third ofthem were over 55. This printout from the Food andDrug Administration records 1,1140 reported adverse drug reactions toproducts containing PPA Thirty percent:313 of the reported cases were from personS over 55. The reactions range from headache tostroke to kidney failure. Forty percent of the reports of cardiovascularproblems were from those aged 55 years or older: [See app. 2, p. 259 for materialsubmitted by Representative Oakar.1 Ms. OAKAR. Dr. Wolfe; you mentionedthat of the over-the- counter drugs that the FDA haschecked out; two-thirds of them proved unsafe and ineffective? Dr. WOLFE. One-third of thetop-selling over-the-counter drugs; almost one-third, have ingredients whichthe FDA believes lack evidence of safety and effectiveness. Based on our own review, When we sentthis information all over the country to various medical experts oncolds and stomach prbb= !ems, we would add another third. Oneof the biggest ingredients in the second third, the one that FDAthinks is safe -and effective but which we don't, is PPA, phenylpropanolamine.There are a lot of other ingredients. So that when youadd this up,_ what we're talking about is that of the best= selling productsin the country, the top 466 drug, two:thirds of them; slightly overtwo - thirds; contain ingredients which the FDA or our experts orboth, think lack evidence of safety, effectiveness, or both. MS. OAKAR. Well, if this is true in so manyoverthe-counter drugs that are sold not only indrugstores, but in grocery stares and all kinds of little outlets- - Dr. WOLFE. Airports: MS. OAKAR [continuing]. Airports,where pharmacists or no one with an insight into the medicalbackground is around, what should be done about those that havealready been proven_unsafe and ineffective? Should we make themprescription drugs? My bill addresses the gap that Cathy mentionedin terms of over-the- counter drugs, the fact thatit's voluntary to report adverse reactions on the part of the drugindustry: But what would you suggest we do for the Americanpublic? Dr. WOLFE. Well, one symptomabout -what should be done can be seen, as you mentionedearlier; in the FDA not showing up. We are currently in- the U.S. Court of Appealshere. We have filed suit against the FDA because we believethat the 1962 drug law which, as you mentioned,requires proof of effectiveness, and whichis now 21 years old, is being rampantlyviolated by the fact that all of these drugs, with ingredientslacking evidence of effectiveness, are still on the market even though aslong as 6 or 7 years ago panels of experts called in by the FDAfound many of them to be lacking evidence of effectiveness or safety. The outcome of this laWSuit is_certainly onething which might push the FDA. We won or at leastsettled favorably a similar law= 55 suit on prescription drugs where; again; we were arguing that the FDA was violating the 19(i2 drug effectiveness law in allowing hundreds of prescription drugs, also lacking evidence of effectiveness, to be on the market. The remedy which the FDA settled out of court was to add staff, not very complicated; to set same deadlines; and to put top priority on the drugs that were the biggest sellers, instead of just the opposite, which was going after the small guys and then wait- ing on the bigger ones because they had more lawyers in Washing- ton. We would hope- the same kind of tight time schedule, increased staff, whatever else, might occur for the over-the-counter drugs. Otherwise, people are really getting defrauded. As I said, one-third of the top-selling drugs have such ingredients. But if you look at just the ingredients alone, because the FDA review really doesn't look at products; it just looks at ingredients, fewer than one-fourth of the ingredients which have been reviewed are safe and effective for their intended uses, and that's why, as I mentioned earlier, in many ways we are still back in the snake oil days. If anything, we're worse off in the sense that instead of a little wagon called "the medicine show" which only reaches as many people as can crowd around it; we have television which is able, through false and misleading advertising such as has been mentioned this morning, to reach millions or tens or hundreds of millions of people with messages implying or stating explicitly_ things that aren't true. And the Federal Trade Commission is 10 years behind on many of these and, in some cases, hasn't done anything. So, I think one remedy is really to push the Government agencies, the FDA and the FTC, to stop breaking the law. They are breaking the law. That's what we're arguing in the Court of Ap- peals here. Ms. OAKAR. Thank you. Mrs. Sachs, thank you for coming. You indicated in your testimony; that you had a cerebral hemorrhage: Would you use the microphone? Thank you. Mrs: SACHS. Yes, I did. Ms. OAKAR. And you are still feeling the after effects of that difficult period? Mrs. SACHS; Yes; I really am in many ways- MS. OAKAR. And what was your health like before you started taking diet pills? Mrs. SACHS. It was extremely good. It was You know; _I needed to lose a few pounds, but nothing terribly bad. It's just that my son was getting married andl wanted to look good, and I thought I'd lose an extra 10 pounds. Before that my health was excellent. And I still don't have high blood pressure or any of the other illnesses. Ms; OAKAR. You did not have any of the systems described on the back of the package, in that fine print? Mrs. SACHS. Nothing. No Ms, OAKAR. It says if you have hypertension and any tensions like that you shouldn't take the drug. Mrs_SAcHs. Nothing like that; no. Ms. OAKAR. Did you say you're 61. Mrs. SACHS. I was then, yes. Ms; OAKAR. How old were you when you took it? 56 Mrs. SACHS. I was 61 when I took the pills. Ms. OAKAR. When you took the pills? Mrs: SACHS. Yes. Ms. OAKAR. Did your pharamacist recommend Dexatrim to you? He indicated that you ought to try this; is that right? Mrs. SACHS. Yes, he did. Absolutely. Ms: OAKAR. I see: And he didn't ask your age or anything of that nature? Mrs. SACHS. No, he didn't. And when I went back later and told him I had a cerebral hemorrhage; he just laughed the whole thing of - Ms. OAKAR. He laughed the whole thing off? Mrs. SACHS. He said it must be inherited or it must be in the family. He wasn't going to admit anything.-- Ms, OAKAR. I would like to commend Howard Babbush and submit for the record the legislation he introduced to forbid over- the-counter diet pills from being sold to minors. I admire his courage; I understand that the legislative body -was under pressure from the diet pill manufacturereven though that manufacturer claimed that they did not want the pills sold to minorswho lob- bied heavily to defeat the Babbush bill. [Material submitted by Representative Oakar follows:] 57 STATE OF NEW YORK

807

1983-1984 Regular Sessions IN SENATE (Prefilid)

January 5; 1983

Introducedby _Sens. BABBOSH, BARTOSIEWICZ, BERMAN, CONNOR, CALIBER, LAVALLE, MARKOWITZ -- read twice and ordered printed, and when printed to be committed to the Committee on Health

ANACTto amend the public health law, in relation to the sale of phenylpropanolamine hydrochloride In diet pills or liquids

The People of the State of New York, represented in Senate and 45-sum bly, do a. follows.

1 Section 1. The public health law is amended by adding a new section 2 thirty-three hundred eighty-four to read as follows:

3 - § 3384; SaIe_of substance_containinI phenyIpropanolamine hydrochloride 4 (phenylpropanolaMine liCL).I. It_SIM be Unlawful for any pharmacy or 5 other retail establishment to sell to Any person under nineteen yearsof 6 a e an ills-or-li uids labeled as intended for dietinor wei ht loss 7 chloride td.ulipx.aUsn mine 8 HOLI-uniess-,--inthe cas ed by_1 9 licensed physician. 10 2. A violation of this_section_shall be e_misdeme4nOr. _ II § 2. This act shaII take effect on the first dayof September next 12 succeeding the date on which it shall have become a law;

EXPLANATION -- Natter in italics (underscored) is new; matter in brackets . ( ) is old law to be omitted. L8D04066-01-3 58

cu_ Croori CO...Mose C ( 17 .1.11.1.C ....a_cu 134.akliwg Of ....kW.. _. .5...../...1..,,,..- -- __. 00.4CI .M.E1-461,, COC., LIP,__ 11110 THE SENATE 1Vg1CCI C....M11. to C...... ,. IV. 1,11,16 STATE OF NEW YORK CliftPle:rani SPOW.Ms.0... II!1:10.1 I 417-,--11100/ MEMORANDUM Senate 1 807

AN ACT: health law; in relation tothe to amend the public dispensing of certain substances.

SUMMARY OF PROVISIONS: This bill provides that over the counterdiet pills and appetite suppressants Can net be sold to aminor under the age of 18 without a detter'S prescription.

JUSTIFICATION: Many school age children who may beWiaware_tbat_they_are hypertension victims, or who have a prierhistory_of tachycardia, are buying over the counter-diet pills,not_for_weight redurtion, can_be_obtained_by the high level of but to obtain the "high" that In caffeine and other_dheMiCaIs_included_inthese compounds. pills to reseMble_ addition, theSe_Children_repack the_dietthe street to other miners a prescriptien drug_and_sell_them on Who AlSo USe them_to obtain a "high'. The Federal GOVernment_ it few_investigating ways in which overthe Counter Siet_pills and other "look_alikes" can beprohibited; In_the interim, before comprehensive legislation_canbe_developedi_it is essential to restrict sales.--At present,diet_Pills_are as accessible but children_end teens who_use them toobtain a as candy; BedaUSe quick " high " -may be_putting themselvesin serious danger. a comprdhentive_plan could:bemonths or years away, this temporary telfitien is essential to protect minors.

FISCAL IMPLICA None

EFeECT/VE DATE: effect on-the_firstday of September This act Shall take shall have become a law. next succeedingthe cate on which it 59 Ms. DAKAR: Let me ask Mrs: Davis; you were a stroke victim and I notice that you are still wearing a brace as a result. Is that as a result of the stroke that you had? Mrs. DAVIS. Yes. DAKAR.AKAR. And I have your doctor's testimony, who could not be here with you today. But did you have any health problems before you took diet pills? Mrs. DAVIS. No. Ms. OAKAR. And your doctor wasn't aware of any? Mrs. DAVIS. I had just had a baby about 6 weeks ago; and I was 26. Ms. OAKAR. But you had had your child. Mrs. DAVIS. Yes. Ms. OAKAR. It does say on the package that if you are pregnant you should not take this. Now; what did you do? You appealed to the drug company and then_ when you got no satisfaction you took them to court? Is that what happened? Mrs. DAVIS. No My Congressman had wrote, you know, when I done wrote them I didn't get nothing from them. So I got my lawyer. Ms. OAKAR. And they settled out of court with you? Mrs: DAVIS. Yes. M. OAKAR. Would you like to tell this committee how much you were able to get? Mrs: DAVIS: $1;000 what was it? MS. ZACKERY. $125,000. OAKAR. But your health will never be the same, will it MrS: DAVIS. No MS. OAKAR. I See. Now, you attribute the problem you have now and the stroke that you had to these diet pills; is that correct? Mrs. DAVIS. Yes. Ms. OAKAR. Thank you very much, Mrs Davis. 1VI& Phipps; you're a nurse. You gave us some technical-scientific data in your report. Did you go to a doctor when you noticed your heart beating so slowly? Ms. PHIPPS, I noticed that my heart was beating very slowly and I went directly to the hospital. Ms. OAKAR. And what would you say actually happened to you? Ms. PHIPPS. The way the physician explained it to me, that my blood pressure was elevated and the end result, it caused my heart to beat-slower than normal: Ms. OAKAR. Kathleen, you gave us a tape. Did you have pressure placed on you as a result of your work as an investigative consumer advocate? Mrs. O'REILLY. Personally? No. I did not. Ms. OAKAR. Did you have any threats of lawsuits or anything of that nature? Mrs. O'REILLY. Not that I'm aware of. The legal points that Ide- scribed -were submitted by Thompson Medical to NBC and we responded to therm OAKAR. You have with you Mr. Adamo. We were a little remiss in not having you at the panel: Are you suffering? You're a

64 60 reasonably young man: Are you suffering from any after effects as a result of the stroke you had? Mr. ADAMO. Fortunately my residual effects are very slight in that I_ have numbness in the left side of my face and the back of my left ariii. Those are permanent and, like I say, I feel very fortunate that I do not suffer with more serious and permanent types of reactions from -my episode. Mg. OARAft. Mr. Wortley? Thank you Mr. WORTLEY. Thank you; Madam Chairman; I'd like to make an observation for Dr. Wolfe and Mit. O'Reilly. In a recent edition of the International Journal on Obesity, an article entitled; "Three Controlled Trials of Weight Lass with PPA," indicates that patients taking PPA lost significantly more weidlit than those taking a placebo, 4.64 pounds compared to 2.07 pounds; In other words, that's about twice as much. Would you agree that this would Seem to establish the effectiveness of PPA for losing weight? Dr. WOLFE. Well, I don't think anyone said that PPA doegh't work at all over a short period of time i don't know what article you're referring to or who paid for it or who did it, which makes a big difference in terms of evaluating it, But what has not been proven is the long-term effect over months and months; as is recommended by the company. If people eat less, with or without PPA, they will lose weight. That is something that thousands of years have shown to be true; The question is long-term effectiveness and if you're taking it for a lohg time, the risks obviously increase over wilat they would if you were taking -it -for- a short time. _ As I say, I don't have the article. I don't know which one you're referring to. Mr: WORTLEY; I have the article here; It came from the Medi-cal College of Pennsylvania. Dr. WOLFE. Who was it sponsored by? Does it say that? Who paid for the study? M.S. O'REILLY. And what is the date of it? Mr. WORTLEY; April 1_3; 1982. Dr. WOLFE. Mr. Wortley, I would be glad to look at the study and Submit comments on it, if that's what you would like. Not at this moment_because other Mrs. O'REILI.V. A subsequent panel this morning_of experts who are very familiar with the specifics of each of these studies; I'm sure will be able to respond to the points. Mr. WORTLEY. SO you think PPA is safe as an effective nasal decongestant? When it's used in a spray form? Dr. WOLFE. In the book I mentioned this morning, "Over=the= Counter Pills That Don't Work," we discuss at some length the use of oral decongestants; whether it's PPA or phenylephrin citherS, and the point we make is that first, if you've got a cold and you just have a runny nose, you shouldn't really use any kind of decongestant; If you really have a blocked up nose and Might be at an increased risk of having an ear infection, for instance, especially if you're a child, it may make sense to use a decongestant. Why take 50 times more decongestant, which you would take in an oral form, such as Contac, for instance, as opposed totaking 61 one=fiftieth the dose in spray or nose drops? Nose spray and -nose drops can't be used for more than 3 days or you can get side effects from them. But the point that was made earlier is that one thing Which differentiates oral decongestants with PPA from the diet pills; is that you're going to use them for a much shorter period of time. That is true. But we would add; why use them at all when you can use one-fiftieth the amount in a nose spray or a nosedrop form, reduce the safety risks, if you only take it for 3 days, or less; Frequently people only need to use it for I day. Mrs. O'REILLY. And our segment specifically recognized the generally accepted principle that PPA, used in a cough; cold remedy; and so forth; has generally been found to be safe and effective as a decongestant. And Dr. Prout, who you will be hearing from, who is acknowledged by the court, in the Porter-Dietsch case; as an established medical expert, could probably elaborate on that. Mr. WORTLEY. We'll look forward to his testimony. I yield back the balance of my time. __ _ Ms. OAKAR. Thank you. If I might just say for the record, the thrust of this hearing is on diet pills. We don't want to take Mr; Lantos' Contac -pill away from him. Mr. Lantos? Mr. LANTOS, Thank you very much and I appreciate the Chair's assurance that I'll be able to take Contac in the future; I sort of am interested in the anecdotal testimony that we have received from some of our witnesses, and obviously my reaction to them, as I tak,it everyone's reaction to them; is one of empathy and sympath': and concern and understanding. Each of you have had medical problems. There may or may not be a cause and effect relationship between your taking pills and your medical problems. But whatthink is obvious, and I was particularly intrigued by ur testinic:', is that on the basis of your experience you are rec- omrnertding _that all over-the-counter medications be removed which have PPA, and I do not think that you have the qualifica- tions to make such a judgment. Dr: WOLFE; That ;,s why i say it is my judgment. Mr. LANTOS. Well, I understand that but there -are 230 millicm people in this country and everybody has his judgments, and in various fields such as airline safety or the safety of drugs, we are dealing with experts. So, I would like to confine my questioning to Dr. _Wolfe_and to Mrs. O'Reilly, who I take it is an attorney? Mrs. O'REILLY. That's correct. Mr. LANTOS. You have no training as a physician? Mrs. O'fiziLLY. I do not. Mr. LANTOS. And you have no training as a scientist? Mrs. O'REILLY. That's correct; Mr. LANTOS. You have training as an attorney? Mrs. O'REILLY. That's correct. Mr. LANTOS. Having a daughter who is an attorney, I have high regard for your training in the legal field. Dr. Wolfe, I'd like to ask -you to address the question of obesity as a serious problem in the UnitedStates. The figures I have seen, and I have, as I always do, prepared myself for this hearing. The figures are in the neighborhood of 80 million Americans, depending on how you define obesity.

27-436 0 - 84 -5 62 It's self-evident that a broad spectrum of problems, from cardiovascular diseases to cancer are related in varying ways and -in varying degrees to obesity. Studies show that overweight individuals have- a much higher likelihood of developing these diseases, of dying of these diseases. Is it your testimony that over-the-counter diet medications have no value? Dr. WOLFE. My testimony is a little bit different than that. Every drug, assuming that it has some effectiveness, has -a_ benefit and _a risk. And when one decides on whether a drug should be on- the market in the first instance, when it first is up for approval, or whether it should be removed, you balance the benefits and the risks. In the case of PPA, the benefits are too small in com_parison with the risks; for it to stay -on the market; in my _judgment; as an over- the-counter drug, and I think you will hear that from a number of other physicians, as well as from victims. I think that the victims who have suffered in ways that they believe are associated with the drug - -- Mr. LANTos._Could I stop you there? Ur. WOLFE. Yes. They have as much right to speak out as I_do; Mr. LANTOS. Well, everybody has the right to speak out in a free society. The question I have; which as a logician disturbs me, is that we have testimony of cerebral hemmorrhage, of strokes; and every one of these instances is a tragic human episode. My question is are there studies indicating that you are aware of;_that, for instance, strokes occur more frequently in that segment of the population that takes diet pills than in the segment of the population that doesn't take diet pills? Dr. WOLFE. There has not been that large kind of prospective epidemiological study. I'll tell you, Congressman Lantos, the thing that concerns me the most was the study I mentioned briefly before-- Mr. _LANTOS. But could I just-- Dr. WOLFE. Wait. I'm answering your question. Mr. LANTOS. Please go ahead. Dr. WOLFE [continuing]. The study in perfectly normal people; medical students, as I said, if medical students can be deemed as normal. They did.not have any high blood pressure. And when they took amounts of this drug that are pretty much in the same range that we're talking about a number of them had dangerously high elevations of blood pressure after just one pill. If this were to happen in an older person, I could well imagine that might be one mechanism whereby they r ould have a stroke. So, if you take a very well-controlled study on normal people and combine it with a series of anecdotes, as you call them. in which people very shortly after taking one or more of these pills; have a stroke or something else, the evidence begins to mount. Whether or not we're going to have the perfect study that you are suggesting would be nice to have; and I would agree; is a different question, and whetheL or not we should wait that long and have more and more anecdotes and more and more strokes until then, is another question. It's an ethical as well as a public health question. 63 The reason more and more people are suggesting let's get this stuff off the market as an over-the-counter weight reduction pill is that they think that even though the evidence isn't perfect, it's enough to take some action: Mr. LANTOS. You see, the difficulty with the anecdotal evidence to a layman such as Mrs. O'Reilly or myself, who are not trained in the realm of medicine, but in other fields; at least I have difficulty with this, in that I could visualize a panel of four individuals with equal sincerity relating to us how, having been obese, they had a great deal of difficulty in their personal, social; economic lives, as is obviously the case in American society, and by the successful results that they obtained, through taking these over-the-counter medications, as prescribed; they are now psychologically, socially, economically and every other way functioning in a much more happy; satisfying; fashion. Therefore, the anecdotal evidence, although it evokes empathy and certainly sympathy in many instances, as far as this Member is concerned, is of no relevance with respect to the issue of devising public policy Dr. WOLFE. You're talkingabout the anecdotes that people say they feel better_because they have lost weight? Mr. LANTOS. No, I'm not talking about-- Dr. WOLFE. Those are anecdotes that are all_right; is that what you're saying? There are two kinds of anecdotes? Mr. LANTOS. No, I am not suggesting that. And I am surprised that that was your interpretation of what I am suggesting; All I am suggesting is that anecdotal evidence, pro or con, is interesting and worthwhile insofar as that relates to specific individuals. What we are dealing with is a substance which is taken by millions and millions and millions of Americans on a regular basis. I do wish to go back to Contac, because never having taken a diet pill, I can't have anecdotal experience to relate to you. But I can with respect to Contac. It is probably my failure to read the label carefully; but I can't tell you what manufacturer manufactures Contac. I don't know. What I do know is that it has been very effective. It has been very effective and it contains PPA and I, as a citizen, would be deeply resentful of the FDA were it to remove it from the counter, from the Safeway grocery store counter; where I buy my Contac as I need it, because I believe that I and millions of others, having a bad cold, can make an intelligent judgment as to whether we wish to take them or whether we don't wish to take them. Dr. WOLFE. Who recommended removing Contac from the mar. ketplace? I did not recommend removing Contac. Did you think that I did? Mr. LANTOS. But it contains PPA. Dr; WOLFE. Yes; but the recommendatiln was; as I guess I didn't make clear that when you look at a product you balance the benefits versus the risks. When you're looking at PPA in diet pills, I believe, and many others do, that the risks overbalance the benefits, and it is in that specific sense that we are recommending that it should not be allowed. Mr. LANTOS. Yes, but- - Dr. WOLFE. You're raising a different kind of issue. 64 Mr. CANTOS. No, I'm raising an identical issue, and the issue that I am raising is that there are millions of people whovoluntarily take these, purchase these 011s, take them; andpresumably find sufficient benefits _from them that they keep buying theM, they keep telling their friends to buy them. Otherwise there would not be 10 million or whatever the figure is; people who take them. Dr. WOLFE. Well; let me just respond to that The So--called mar- ketplaee test which you're_ raising, and which many _othersraise- people in the drug industry; is not valid for a number of reasons. One, many products contain more than oneingredient and its possible that one ingredient is what is workingand the additional one isn't_That's why; as I mentioned before; mostof thote products, many of the products on the market now, are illegallyin the market as-far as we're concerned; because they mayha...'e four ingredients. Three may be effective; one may be nOt. The marketplace would say this works; let's keep using it. But themaiketplace would be glad if it got the three instead of the four, possiblyfor a lower price. Mr. LAirroS. I think that's a very v.-, lid point. Could I stop you on that? DT. WOLFE. You can stop me wherever you want. Mr. LANTos. If there are four ingredients and three areeffective, and the fourth-- lar. WOLFE. IS not. Mr. LANTOS. Is not effective; even _dangerous, what is thebenefit from the point of view ol the manufacturer, of insisting onretain- ing the fourth, dangerous or ineffective, ingredient? Dr.- WOLFE. I think you'd have to askthe manufacturert. My answer would be that one of the reasons wehave 300,000 different oVer-the=,counter drug products is that the thing thatdifferentiates most of them from one another is the additionalingredient, lacking evidence of safety and effectiveness. The thing that is uniqueabout Anacin is that Anacin has caffeine in it. If they had to say, when you saw an Anacin ad,"Anacin is just plain aspirin," do you think that they would sell$60 million, $70 million worth a year? So -the answer to yourquestion it that the market fixture of many of these products is based onthat additional ingredient and they don't wa :t to _let goof them very readily. They will be forced to let go of th::tri when theFDA finally requires these ingredients to be removed from the marketbecause they lack evidence of safety or effectiveness; So; the answer is that companies know they can keepselling and making money from these products that are even though the uniqueness is with an ineffective ingredient, andthey therefore will do it. Mr. LANTOS. Are you suggesting that the use-- Ms. OAKAR. Excuse me. Would you just excuse me,Mr. Lantos, for _1 second? We do have to leavr this ro:im at 1 o'clock.We have a team of med'cal experts rrt bLialf of the industry and thosewho may or May not the industry. I would really like to limit the time now, if ,,ve could. I think some of the questionsabout eldies can be addmated tc theindustry and to others who are medical ex- ho have done the appropriate studies. 65 Mr. LANTOS. That's fine, Madam Chairman. MS: OAKAR: Thank you; Mr: Lantos. Ms. Ferraro? Ms. FERRARO. Might I suggest; Madam Chair; that perhaps we should observe a 5-minute rule for each of the members during the course of the questions? Ms: DAKAR: Right After you we will: Ms. FERRARO. Well, I'll keep myself down to 5 minutes. I just wanted to s:iy to Torn that I'm sure Safeway and Contac are delighted by his endorsement today; and I'm going tee subject him to another anecdote. When I stopped smoking, about 14 years ago, I put on a pound here and a pound there and a pound every- place else, and decided I was going to lose 10 pounds and went to take diet _pills. And what I did wasit was amazing. I can recall taking them for like 3 days and my heart started beating very fast and I cleaned my house as if I was a commercial for the white tor- nado. I mean I just wentI couldn't believe. I'd be up very early in the morning and I couldn't sleep at night; And I decided that I didn't want to become a nervous wreck, so I stopped taking them and immediately upon stopping taking _them the symptoms stopped. Of course, I didn't lose any weight. But at least I was not a total wreck. Now; I am a very healthy person; I had never had a problem with shortness of breath or any of those other things that started and stopped with the start and stopping_ of the diet pill. I don't like those things and I would like to see them off the market: But I just want to question Ms. Phipps. Had you not been a nurse would you have recognized your symptoms as being dangerous? Ms. PHIPPS. Probably not. Ms. FERRARO. Had you not gotten medical treatment as quickly as you did, what would have been the result? Ms. PHIPPS. Possibly a stroke could have happened. It's very hard to say:_But probably a stroke: Ms. FERRARO. In any of your cases had you asked for doctor's supervision while you were taking those pills? I know I didn't: So; you knowdid you? Ms. PHIPPS. No, _I did not. Ms. FERRARO. Had you; had any of you; had doctor's supervision while you were taking the pills? Mrs. SACHS. No. Ms: FERRARO: Na? Had you hadhad you been to the doctor just previous to that? You were pregnant, Mrs. Davis, so you had been to the doctor. Mrs. Davis. My baby was already 6 weeks old, Ms. FERRARO. Oh, so it was after the baby. Sc you had already been back for your checkup and everything else and you were in good shape. Your blood pressure, when the doctor checked you, was not high at that time? Mrs:_ DAVIS: No Ms. FERRARO. At your checkup after the baby? Mrs. DAVIS: I started taking pills after my baby was 6 months old. MS. FERRARO. OK. 66 Mrs. DAVIS. Six weeks old. Ms. FERRARO. Six weeks old. But had you gone back to the doctor for yourvisit after having the baby? Mrs. DAVIS. No. Ms. FERRARO. No; but when you were in the hospital your blood pressure was OK? Mrs. DAVIS. Yes. Ms. FERRARO. So you had not had a problem. So there was no history and it was rather a recent check that you had not gotten high blood pressure before that point. It was one that you feel that was connected with taking the pill. Let me ask you; Dr; Wolfe; you do not suggest taking every drug off the market that has PPA, do you? Dr. WOLFE. We haven't made that suggestion. As I said, in this book what we've said is that we think that its safer and as or more effective, when we're talking about the nasal decoongestants, which is the other big category of drugs that have PPA, to take the spray or- the -drop form. But we have not suggested taking that form of PPA off the market. We agree that it's a much shorter period of use, a day, two, three, as opposed to months or longer, and therefore tr.o risks are fewer. There have been problems associnted with it;ut the whole nature of the use is such that the problerrk;.c I don t think, are as great as with the diet pills. Ms. FERRARO. With the diet pills; it seeao to me that you would not want to eliminate totally an accessory fbr appetite control from the market. But it's just the fact that you'v- #.toncerned about these particular accessories, Dr. WOLFE. Or their predecessors. Amphetamines are the predecessors. Ms: FERRARO. Well; the question is how- does the FDA get to the point where it can allowwhat are they doing wrong in testing, in your view? Dr; WOLFE. Well; the FDA doesn't_do anything wrong in- testing because they don't do any testing. What goes wrong is that the tests that are submitted by the com_panies are often_poorldone. One of the reasons why it takes drugs longer to get on the market is that the FDA has to send back to the companies poor quality studies. In this case -I think that a mistake was made by the panel of experts who-evaluated the studies, particularly on the safety of these drugs, and to some extent on the effectiveness. And I believe that this hearing is going to provide a reason for reopening those hearings. Ms. FERRARO. But my point is this: That there's obviously something wrong with- the procedure for -this to get through and for other, even prescription drugs, to get through. Dr. WOLFE. The scope of use has increased a lot. I agree with the statement that the FDA -has a lot of dedicated civil servants; Most; if not all, of them are. But the problem is that when the decision was made on this ingredient, the use was nowhere near as extensive as it is now and; unfortunately; it has taken that widespread use to collect the amount of information that is now collected. So, I 71 67 think that they might make a different decision today, and I hope they will. Ms. OAKAR. Could I just correct one thing? There is no decision on these drugs. Dr. WOLFE. It's not beenthere's no final monograph yet. Ms. OAKAR. That's right. Dr. WOLFE. Bat their tentative decision was to say that it was in category 1, or safe and effective. Ms. FERRARO. Well, it seems to me that the committee should perhaps look at some oversight as far as what the FDA is doing as far as their procedure is concerned. It's not up to us to take a drug off the market. it's put to them, to make sure that it's safe before it's _put on the market. Thank you, Madam Chairman; Ms. OAKAR. Thank you And I want to thank the panel, particularly the victims, who came from all over the country to be with us today. It was a hardship to get here; Thank you very; very much; I would also like to submit for the record some letters I have received from other victims of diet pills. 25 STONEGATF ROAD, Ossining, NY , Jaly 22, 1983. Mr. DANIEL ROSENBLUM, Staff Assistant Congress of the United Stales. Washington. D.C. DEAR MR. ROSENBLUM: As per my husband's telephone conversation with you, I am submitting a statement Which I hope will help you-at the hearing. Sometime in September 1981, I had decided to take Dexatrim to lose weight. I had taken about 5 or 6 pills over a period of 10 days. One morning I began thave these violent headaches and nausea. I have never had this feeling before. The 'Mowing day, I went to work w_hen again this feeling came over me. One of my co-wo kers took me to my doctor Upon examining me and my telling him what I had taken and the symptoms I had; Dr: Heckman thought it might have been from the Dexatrim. He told me to go home and rest. He would not prescribe any medication, for fear of triggering off another headache. That evening every hour on the hour, I kept having the headaches and nausea. The following morning, upon awakening I again started with the same headaches. I was sitting in bed and m_y hands became paralyzedthey were in _a locked position. at which time I thought I was having a strokei_or dying. My husband and I became hysterical. He immediately called Dr. Beckman who informed us to go to the hospital where Dr. Weintraub; a neurologist would meet with us. Dr Weintraub felt after examining me and his past experience with this type of case, my condition was due to the Dexatrim. I am very sorry that I am unable to appear at the hearing, but -I wish you every success in your crusade and if there is anything more I can do, please do not hesitate to call. Very truly yours, LORRAINE MICHAELIS.

BRUCE H. HECKMAN; M.D., MPH.; Ossining, N.Y; July 19; 1983 Congresswoman MARY_ROSE OAKAR, 24,16 floyburn Building. Washington; D. C DEAR CONGRESSWOMAN OAKAR: Mrs. Lorraine Michaelis had the onset of a severe pounding headache on 9/30/81. She was seen by me on 10/1/81 with hot sweats, nausea, vomiting and some diarrhea. _She also had some pain in the upper chest. She was given Florins! with no real response. The headache became severe again on 10/2/81 and she was seen by a neurologist in emergency consultation; Dr. Michael Weintraub. Ail electroencephalogram and computerized tomography of the brain were performed and were normal. Slowly the headache dissipated over time 72 68 The feeling of both Dr. Weintraub and myself is that Mrs. Michaelis' headaches were- precipitated by taking an over-the-counter "diet pill" containing phenylpropanolamine. It is my opinion that these medications should be removed from the market since their potential for causing life-threatening illness and abuse far outweigh its long- term beneficial effects in weight loss. Sincerely, BRUCE H. HECKMAN, M.D., MPH.

MICHAEL I. WEINTRAUB, M.D., F.A.C.P., P.C., Briarcliff Manor, NY., July 17, 1983. Hon. MARY ROSE OAKAR,_ Congress of the United States; House of Representat..yes; Washington, DC. DEAR _REPRESENTATIVE OAKAR: I am sorb, that I could not attend your hearings. In my discussion's with Daniel Rosenblum; he indicated that a letter might be of some benefit to ,)u and your committee. Briefly PPA is an active ingredient,in diet pills and vta.r combined with caffeine: Its alleged action is "to help people lose weight" in Illation with an appropriate diet. This drug has a similar chemical formIda 1. ohetamine, which is "speed" or an "upper." These pills achieve a high by stimulatory effects on both the brain, heart and musculo-skeletal systen) Illus. it is not surprising to see some bodily, response to this medication, ba .1 on dosage but also individual sensitivity. In the medical literature headaches, rapid heart rate, arrthymias, palpitations, convulsions,. psychosis and death have been reported. Many people; in fact the majority; do not consider this medication when questioned in routine medical- examination. They are unaware that these pills may produce bodily changes, rather -than the "alleged" weight reduction. Thus it is not uncommon that physicians in practice will encounter patients who are on these pills and who may be symptomatic with some complications, thereof. I have been exposed to sioveral patients who have encountered complications with PPA. As you know I interpreted a CAT scan on Lorraine Michaelis who was sent by her physician for 1.ney :fo-rod headaches; to rale out stroke_and tumor. This test was normal and I so,),,zht her anxiety about these results. as we spoke she informed me thai, she was taking dexatran, etc. and experienced severe headaches, sweating and pupillary dilation. I told her that this was probably secondary to her diet_pills, because of the slim :story structure of the medication. I also informed her that I had other patients who had some neurological symptOms as a result of this medication. I did not formally evaluate Mrs. Michaelis but only performed a CAT scan at the request of her physician. As I mentioned I know of other complications with PPA induced convulsions. It is not surprising- that this "mild" stimulant would achieve a "moderate or severe" stimulating effect on the grain cells which can -produce a spectrum of a "high" or jitteriness or convulsions or hallucinations or frank phychosis. Often these drugs produce observable rhythm changes on the electroencephalogram (EEG) and I have seen this. One of my patients,- Donate Taylor, who was previously healthytook PPA to achieve weight loss. She had grand ma] seizures with EEG changes. I believe that PPA included a stimulating bombardment of irritation tahex brain cells that ultimately culminated in her having convukions: The cells became so overwhelmeelin a susceptible individual, that they released all their- energy into a clinical seizure. Many patients show excess beta activity on their EEG while on PPA: The brain centers for cardiac function can be stimulated by PPA and they produce cardiac irregularities which can culminate in death. Recently-we had a teen- ager who took an overdose of Dexatrim and was admitted to theICU for this cardiac arrythmia. She almost died. As you can see there is a broad spectrum of clinca! responses that any individual may develop and there is no way to predict_ who_is suspceptible and atwhat strength of dosage. As with any medication; abuse occurs and consequently withdrawal states can arise when the medication is discnntinued. I feel your committee has- an important task and should arrive at a decision requiring a prescription for this drug. I also feel there -is a more important overriding issuedo these pills serve any purpose and specifically do they achieve weight loss. To the best of my knowledge there is n o m edical evidence that statistically demon- strates_that_these pills work better than placebo, diet, exercise etc. Since overweight status and obesity is a multifactorial phenomena that is chronic, how does a three

73 69 week trial serve any useful purpose? I strongly feel that your committee recommend that a multi-center short term trial be set up* under government supervision in NIH; with age-matchsd; psychologically matched, weight-matched controls to determine if these drugs are effective. The results of this study; including complications; will- become clearcut and the appropriate decisions can then be made. The above represents my honest opinions on the matter of PPA. Your reputation for hard work, determination and honesty have my utmost respect. With best wishes. MICHAEL I. WEINTRAUB, M.D., Clinical Professor.

JOHNSON CREEK, WIS., May 14, 1982. FOOD AND DRUG ADMINISTRATION, Dockets Management Branch, Rcwkville, Md. DEAR Sias: Before you make your final decision as to whether or not P.P.A. should be allowed in O.T.C. drugs and medications, I would like to relate what happened to me. I st_arted taking Dietac to lose weight and followed label directions, taking one time-release capsule a day, teach_contained 75 mg. P.11. and 200 m_g. caffeine./ On Jan miry 19, 1981, I suffered with what was diagnosed as_a_strokeHospitaliza- tion and a battery of tests revealed an area of damage to the blood vessels in the right side of my brain. Because I WM only 28; healthy and with no history of medical-problems, ray doctor was puzzled as to the cause. On October 19, 1981, I heard a report on the radio linking P.P.A. usage with high black' pressure, personality changes and stroke. I got in touch with the Center for Science in the Public Interest, who had released the report= They have been a wealth of information. The more I read, the more convinced I became that my stroke was Arobably caused Iv P.P.A. usage. I know I am not alorm There are many people who have suffered medical problems for no apparent reason; except for using_a product containing_ r.p.A. I feel that it there is even the slightest bit of doubt concerning the ,safety of the use of a product, then it should not be allowed in an O.T.C. item. If the F.D.A. is to err in-its decision, it would be much to better to err on the side of safety; and not allow P.P.A. to be sold in O.T.C. products. Sincerely, FRANK ADAMO.

My name is Dnnata Taylor and I am eighteen years of age, having been liorn on Felzwiry 7, 1265, in Port Chester, New YOY k. At the time I became ill about two years ago from taking diet pills, _I -lived_ with my parents, John and Patricia Taylor on Baldwi,L Place in Mahopac, New York._1 was sixteen years of age at the time. I am tall and two years ago weighed about 140 _lbs._ I feltwas over weight and wanted to lose weight; so I went to a local drugstore in Mahopac, New York, and looked around on the for some sort of pills that would help me lose weight. I picked out the Dexl.trim. I chose that brand myself, no one recommended it to me. I followed the directions and began taking these pills according to the directions, one each day. This went on for about one month or one and a half months when I became ill. I had been home the night before and _I believe it was on a -fireekend in April, _1981. I _had a good nights sleep and got up as usual at 7:00 A.M. I suddenly felt tired, really tired, and I want to my room to lay down and go to sleep. This was about 10:00 A.M. I woke up about-2 [lotus later and began to go downstairs to the kitchen when apparently I had some sort _of seizure while going down the stairs. My parents were there and helped me. They called the local ambulance squad and they took me to the Putnam Community Hospital in- Carmel, New York, wher_e_I stayed for-two days. My doctor was a neurologist; Dr Michael Weintraub; who has offices in OSSinmg, New York and Carmel, New York. I remember waking up in the hospi, tal. When I came to I was in a bed in-the hospital and while talking to the doctor I explained to him that I was taking Dexatritn- for about a month or more I was given a variety of tests including an E.E.G. He spoke to my parents more about what had happened to me. The doctor told me that I had had an epileptic seizure and that it was due to the diet pills that I was taking. When I left the hospital after two days, the doctor prescribed medice for me, Dilantin. At first I took only the Di- 70 lantin three times a day and I had more seizures at home: Then the doctor added Depocaine and I took that three times a day; also. Since then, I have not had any more seizures. After I got out of the hospital, I saw the doctor every two months and then every three months and then every six months. He has taken blood tests regularly and I had a Cat Scan and a Spinal Tap. 1 ;.pink they were done about one yew- ,:fter I was released from the hospital. During the last year I have not had any more seizures but I have to take hoth medications three iimes a day. Dr. Weintraub told me that _I will have to take the medications for the rest of my life. Early in 1983, I moved from my parents' home to live with my grandmother; Rose Lanza; Eruct still live with here at 370 Westchester; Port Chester. New York 10573. One night we -were watching television and we saw that there was a discussion abbut the effects of diet pills on some people like myself. My older sister, Darlene, had also tried these pills at the time I was on them, but she had no problem with them. My grandmother even tried them but had to stop because she did not feel good; possibly because of her high blood pressure or other priablems. By the way, when I was taking Dexatrim, I only log two pounds. When I had those other epileptic seizures at home when I first came out of the hospital, t h e y were pretty violent and m y two older brothers had to hold me down. I have no memory of those seizures but my parents and my brothers told me about them. Prior to having seizures, I was never seriously ill during my life. While I was taking the Dexatrim, I was on my normal diet. I had previously never been hospital- ized or sick except for an occasional cold. I recently saw Dr. Weintraub again an-u'_ he said I was doing okay_ but that I should definitely keep taking the wile two medications three times a day. 1 am now out of high school and I work full time as a wait- ress. I have signed this statement voluntarily this day of July,-1983. DONATA T5. JR

I head a Company with 23 employees. Part of the reason for my stopping to take Dexatrim is that my associates were convinced that the capsules made me "cmay" and impossible to deal with. I myself noticed this effect. I immediately noticed that taking Dexatrim produced difficulty in urinating. _I stopped a day then started again,repeated this several times and was able to confirm the causal connection. First made me think I had prostate problems. I phoned Thompson Medical Co. and spoke to an MD (did not note his name), in order to check this side effect. After a bit of discussion in which he asked me to write them a letter indicating that Dexatrim had helped me to lose weight (thaes true), he admitted that the urinating difficulty side effect had indeed been reported previously, but that this was a temporary effect which would cease when I stopped taking Dexa- trim, which indeed it did. The same MD explained that the tirug_contained in Dexa- trim has been known for decades as a decongestant whose side effects had been ape- tite loss, and that Thompson simply turned this around to capitalize on the side effect. I indicated to him that I had not noticed any decongestant qualities, and that actually need Afrin at times for that purpose: I was not; however; taking Afrin during this period. STEPHEN F. TEMMER. MS: OAICAR Our next panel includes Charles_ Nelson, who is -the Assistant Chiel' Postal Inspector; Criminal Investigations; U.S. Postal Services of Washington, accompanied by George Davis, and Ms. Bambi Young; who has probably done the most extensive study in monitoring the diet pill industry._ She is with the Center for Sci- ence in the Public Interest here in Washington. We wculd like to ask you if it's possible to limit your testimony so that we can get -to questions; Let's say 10 minutes each so -we can really get to all of the panelists, in a spirit of fairness. Mr. Nelson, would you like to proceed? 71 PANEL 2CONSUMER ADVOCATES, C )NSISTING OF f MARLES_P. NELSON, ASSISTANT CHIEF POSTAL INSPECTOR, CRIMINAL IN- VESTIGATIONS DIVISION; U.S. POSTAL SERVICE; WASHINGTON, D.C. ACCOMPANIED BY GEORGE DAVIS. ASSISTANT GENERAL COUNSEL, CONSUMER PROTECTION DIVISION OF THE LAW DE- PARTMENT, U.S. POSTAL SERVICE; AND BAMBI BATTS YOUNG; CENTER FOR SCIENCE IN THE PUBLIC INTEREST, WASHING- TON, D.C. STATEMENT OF CHARLES P. NELSON Mr. NELSON. Yes, thank you, Madam Chairman. I have submitted my fbrmal testimony for inclusion in the record; and; with your permission, I'll summarize that testimony at this time. Ms. DAKAR._ Without objection. Mr: NELSON. We appreciate_the opportunity to appear before this subcommittee to discuss the findings of our joint effort to identify problems associated with the sale of diet drugs through the mails, as well as the Postal Service's role in curtailing the sale and distribution of look-alike drugs. As part of a continuing program to protect elderly citizens; a postal inspector; in the fall of 1980; was assigned to work full time with the members of this subcommittee in a joint investigation of mail fraud schemes perpetrated against senior citizens; One aspect of that investigation focused on the phony weight loss programs and diet pills sold through the mails. We snare your concern about the- health hazard that stimulants and chemical additives, such as PPA, contained in these products may have oil the American public, particularly on the elderly. As a result c our joint investigation, three diet products were challenged under the false representation statute. H & L Labs, Inc. of Norwalk, Conn,- distributed a diet product called "New Quad, plan," containing PPA, benzocaine, and other ingredients, Enclosed with the product was a thousand calorie diet labeled "Quadplar, Diet Menu Plan-" The product was promoted by direct mail advertising during 1980 and 1981. The advertising claimed it to be "The- most powerful reducing aid ever released without a prescription," Prices ranged from $9.95 for a 15-day supply to $38.95 for a 90-day supply. A medical opinion obtained refuted the exaggerated advertising claims for the product. In September 1981, the firm signed a consent agreement with the Postal Service agreeing to modify its advertising. Cove Pharmaceutical Sales of Central Islip, N.Y., promoted a diet capsule and a company diet _plan called q'PAH-Plus," again _via direct mail advertising, from September 1980 through August 1981. The advertisement claimed dramatic, permanent, and immediate loss of fat and/or weight; Prices ranged from $5;95 for a --15 -day supply to $30 for a 120-day supply. The product contained PPA and caffeine. A medical opinion obtained refuted the claims and stated that this combination is ineffective as an appetite suppressant. On August 10, 1981, a false representation order was issued against the firm. A product called "Perma-Loss," distributed by That Special Look, Inc., of Pompano Beach, Fla., contained PPA and caffeine and was accompanied by a sample 4-day diet plan. During 1981, this product, which sold for $9.95 for a 40-day supply and up to-$16.95 for a 90-day supply, was advertised in national publications. Exaggerated claims were made such as, "Now you can shed pounds and inches without dieting. You won't even miss snacks or suffer torturous exercises; or subject your body to dangerous drugs." A medical opinion obtained refuted the product claim8 as false and misleading In September 1981; the firm signed a co-Isent agreement with the Postal Service agreeing to change its advertising. The next subject we would like to discuss involves a product which is not directed at the elderly; but it Aill affects all of us as parents and grandparents because it is targeted at our children. We began our investigation of look-alike drugs in September 1980, after receiving- complaints relating_ to what appeared to be the indiscriminate sale and distribution of controlled substances by mail. Typically, advertisements included full color _photographs of the drug products offered for sale and touted the drug's close physical resemblance to genuine controlled substances. The advertisements often claimed the products offered were 100-percent legal and 100-percent safe. Based on what we believed were material misrepresentations in the advertising for look alikes, administrative actions were initiated against the distributors under title 39; United States Code; section NO& This section permits the Postal Service, following procedures before an administrative law judge in conformity with the Administrative Procedure Act, to withhold and return- to the sender mail addressed to anyone who is engaged in a scheme to obtain money or property through the mails by means of false representations. Between May 1981 and May 1982; -the- Postal Service filed 48 complaints alleging violations of title 39, United States Cole, section 3005. In the complaints filed with the administrative law judges, we -alleged the principal distributors of these look-alike drugs made the following false representations in their advertisements: One, the drug products involved may safely be used by the general public; two, the drug products involved are prepared, labeled, and marketed in accordance with Federal Food, Drug, and Cosmetic Act requirements; three; the drug products were designed for resale to third persons as controlled substances. While I believe the Postal Service has diligently pursued its responsibility in ';his area; I must point out our administrative au, thority in these investigations is limMd to the mail order aspect of these businesses. While initially our efforts curtailed the mail order sales and distribution of these products; many of the major promoters began circumventing the mail stop orders and consent agreementh by continuing their activities outside the mails. Some current advertisements tell prospective customers that only telephone orders will be accepted and that payment must be by credit card, bank wire, or via UPS C.O.D. These procedures avoid- the solicitation of money or property through the U.S. mail; thereby avoiding Postal Service jurisdiction under the false repre-

7 73 sentation statute and rendering any preexisting mail stop orders ineffective. An example of this type of evasive activity practiced byan Ohio- based firm called Brant Pharmacal is shown on the chart now before you. Many distributors have dropped most of their over-the-counter drugs that resemble genuine drugs of abuse. Many have dropped from their advertising the colored pictures of the items being offered for sale. Most have added cautions against use by persons with particular health probleis or conditions and contain specific warnings against resale: There has been a marked reduction in the kind of advertising cited in our earlier actions. The Postal Inspection Service continues to monitor look alike drug advertising and to investigate companies where advertising appears to be false and misleading or to in violation of the administrative orders and agreements which concluded our cases: We thank you for the opportunity to appear before this subcommittee and are prepared to answer questions. [The prepared statement of Mr: Nelson follows:]

PREPARED STATEMENT OFCHARLES P.-NELSON, ASSISTANT-CHIEF POSTAL-INSPECTOR, CRIMINAL INVESTIGATIONS, U.S. POSTAL SERVICE, WASHINGTON, D.C. Mr. Chairman: My name is Charles P. Nelson; and I am the Assistant Chief Postal Inspector for Criminal Investigation& I appreciate the opportunity to appear before this subcommittee to discuss the_ findings of our joint effort -to identify existing problems associated with the sale of diet drugs through the mails as well as the Postal Service's role in curtailing the sales and distribution of look-alike drugs. As part of a continuing program to protect elderly citizens, a Postal Inspector in the fall of 1980, was assigned to work full time with members of your staff in a joint investigation of mail fraAti schemes perpetrated against senior citizens. One aspect of that investigation focused on phony weight loss programs and diet pills sold through the mails: We share your concern about the health hazard that stimulants and chemical additives such as phenylpropanolamine (PPA) contained in these products may have on the American public, particularly the elderly. The Postal Service has been active for many years in attempting to curb false and exaggerated advertising claims relating to the mail order sale of diet products. As a result of our investigations, we have also become aware of the fact that many of the diet products sold by mail contain ingredients which in unregulated doses could be potentially harmful to the elderly, parlic_ularly those with medical- problems. We have on many occasions challenged exaggerated mail order claims- for acle" diet pills containing PPA under the postal false representation statute; 39 U.S.C. §3005, and products containing PPA have been the subject of prosecution under the criminal mail fraud statute, 18 U.S.C. §1341.! Concern over the possible health risk associated with PPA and the misuse of this drug to obtain a "high" are also familiarr. In 1957, representatives of the Post Office Department's General Counsel's Office and the Inspection &rvice testified before a congressional committee concerning false and misleading advertising of weight reducing aids. In the same hearing, the committee received the testimony of Dr. Leon Hirsh of Cincinnati, Ohio, Dr. Hirsh testified that advertising claims alleging that PPA was a "wonder drug" which_ permitted loss of weight without caloric restriction were false, Dr. Hirsh also testified that: Uncontrolled use of phenyl propanalomine in susceptible individuals could produce temporary elevation of the blood pressure; coronary heart attack; mesenteric thrombosis, cerebral hemorrhage and even death. The unrestricted sale- of such a stimulant as phenyl propanalomine, especially when coupled with caffeine, could have profound deleterious effects; In our city, one radio station (WSAI) saw fit to promote this combination of drugs in the late afternoon when high school students would be returning home in their

' U.S. v. Andreachs, 366 F.2d 423 (2nd Cir. 1966). 74 cars with their radios on. The type of stimulating "jag" produced in young individuals; with drugs of this nature is pretty wellknown- I consider the particular product and others similar to it containing phenyl propanalomine potentially dangerous, and not in the public interest and a deteriment to the public health.' In 1978 and 1979, a report was issued to the Food and Drug Administration entitled 'Tentative Findings of the Advisory Review Panel on OTC Miscellaneous_Inter nal Drug Products." The report concluded that_ under particular conditions; diet products containing PPA were both safe and effective as appetite suppressants; Be- cause the validity of scientific claims is tested in our proceedings against the consensus of informed scientific opinion, we have since the release of the report, not -challenged advertising for diet- products in which the claims are consistent with the findings of the advisnry review board. As a result of our joint investigation, three diet products were challenged under the false representation statue: & L Labs Incorporated_ of Norwalk. Connecticut, distributed a diet product called New Qaudplan containing PPA, benzoraine; and other ingredients; enclosed with the product was a thousand-calorie diet labelal "quadplan diet menu plan." The product was promoted by direct.1.,ailadvertising during November 1980 through September 1981. The advertising LI.+, ,J it to be "the MO:A powerful reducing aid ever released without a prescription ,'eices ranged from $9.95 for a 15-day supply to $38.95 for a 90-day supply, a medical opinion obtained refuted the exaggerated advertising claims for the product. In September 1981_,_the firm signed a consent agreement with the Postal Service agreeing to modify its-advertising. Cove Pharmacal Sales of Central Islip; New York; promoted a diet capsule and accompaning diet plan called "PPA±Plus" via direct mail advertising from Septem- ber 1980 through August of 1981. The advertisement claimed dramatic,- pertnar,ent and immediate losses of fat arid/or we-ight. Prices ranged from $5.95 for a 15-day supply to $30.00 for a 120-day supply. The product contained PPA and caffeine. A medical opinion obtained refuted the claims and stated that this combination is ineffective as an ap_petite suppressant On August 10, 1981, a false representation order was issued_against the firm. A product called Perma -Loss distributed by that Special Look; Inc:, of Pompano Beach, Florida, contained PPA and caffeine and was accompanied by a samnle four- day diet plan, During 1981, this product which sold for $9.95 foe -a 4(i-day supply and up to $16.95 for a 90:day supply, was advertised in national publications. Exaggerat- ed claims were made such as 'Now you can shed pounds and inches without dieting.. . . You won't even miss snacks, or suffer torturous exercises, or subject your body to dangerous drugs." A medical opinion obtained refuted the product claims as false and misleading. In September 1981; thefirm_signed a consent agreement with the Postal _Service agreeing to change its advertising. The next subject I would like to discuss involves a product which is not directed at tile elderly; but it still affects all of us as parents and grandparents because it is targeted at our children. We began our investigation of look-alike drugs in September 1980 after receiving complaints relating to what appeared to be the indiscriminate sale and distribution of controlled substances by mail. Typically, advertisements included full-color photographs of the drug products ofTered for sale and touted the drugs' close physical resemblance to genuine controlled substances. The advertisements often claimed the products offered were "100 percent legal" and "100_pereent safe." Samples _of _numerous_Joolvalike _drugs being distributeby mail were-obtained and reviewed by a medical expert. It was determined that Lite), typically contained _a combination of caffeine; ephedrine sulfate; and PRA: Over-the-counter diet products containing some of these ingredien, but not in this triple combination; are available without a doctor's prescription in packaging which contains dosage information and warnings restricting use by persons with particular medical conditions. In a medical opinion provided to the Inspection Service on praducta containing this triple combination of ingredients, Dr. Sorell L. Schwartz of the Department of Pharmacology, Georgetown University Medical and Dental Schools, stated they should "be considered a recognizable danger to public health." Of these particular ingredients, Dr. Schwartz warned that PPA was notably dangerous since it can cause elevation in blood pressure and exacerbate other cardiovascular disease.

_'Hearings befor_e_theSubrommittee on Legal awl Monetary Affairs_of_the House_Comrnittee on Government Operations concerninv,false and misleading advertising of weight reducing aids, A ugust 7, 1957, pp. 123-124. See also Hcuse Report No. 2553, 85th Congress, 2nd session, August 12, 1958. 75 Based on what we believed were material misrepresentations in the advertising for look-alikes, administrative actions were initiated against the distributors under title 39, U.S. Code, section 3005. Section 3005_permits the Postal Service, following procedures before an administrative law judge in conformity with the Administra, tive Procedure Act (f, U.S.C. Chs: 5; 7) to withhold and return to the sender mail addressed to anyone who is engaged in a scheme toobtain money or property through the mails by means of false representations. Between May 1981 and May 1982, the Postal Service filed 48 complaints alleging violations of title 39, U.S. Code, section 3005. In the complaints filed with the administrative law judges, we alleged that the principal distributors of these look-alike drugs made the following false representations-In their advertisements. I. The drug products involved may be safely used by the general population. 2. The drug products involved are prepared; labeled; and marketed in accordance with the Federal Food; Drug and Cosmetic Act 3: The drug products were designed for resale to third persons as controlled sub= stances. A basic premise of the cases was the contention that the offered drug products resembled and were easily mistaken for other illegally trafficked drags containing controlled substances: By language, pricing and other means, the promoters encouraged resale of the drugs by their customers to others. Thus, we believed the sellers were providing their customers, and encouraging them to use, the means to deceive others concerning the actual content of these drugs. The advertisements used street jargon to describe their products such as "blue and clear;" "brown and clear ;" "robin eggs," "714's," "black beauties;" and "yellow jackets." Our evidence showed that those purchasing larik-alikesboth directly from promoters and street corner 'pushers" were junior high, high school, and college-age young people. Of particular concern was evidence of trafficking and use by elemen- tary school children. The 48 administrative complaints we have filed related to look-alike drug- distribu- tors located throughout the country. While I believe the postal service has diligently pursued its responsibility in this area, I must point out our administrative authority in these investigations is limited to the mail order aspects of these business. While initially our efforts curtailed the mail order sale and distribution of these products, many of the major promoters began circumventing the mail stop orders and consent agreementS by continuing their activities outside the mails. Some current advertisements tell prospective customers that only telephone orders will be accepted and that payment must be by credit card, bank wire; or United Parcel Service C.O.D. These procedures avoid the solicitation of money- or property through the U.S. mail, thereby avoiding Postal Service jurisdiction under-the false representation statute and rendering any preexisting mail stop orders ineff-- ctive. An exam_ple of this type of evasive activity practiced by an Ohio based firm called Brant Pharmacal is shown on the chart now before you. Many distributors have now dropped most of their over-the-counter drugs that resemble genuine_ drugs of abuse. Many have dropped from their advertising the colored pictures of the items being offered for sale. Most have added cautions against use by persons with particular health prch:.<7;ns or condition.4 and contain specific warnings against resale. There has been a marked reduction in the kinds of advertising cited in our earlier actions: In fact; I understand that the street term for these drugs is changing from "look-alikes" to "act-alikes." In retrospect, our actions against mail order distribution of look-alikes may prove to have been a useful holding action. Our efforts hopefully gave Federal and State drug enforcement agencies and legislative _bodies time to initiate legal actions and enact legislation which could have a more permanent effect upon the abusive distribution of these drugs. However, the Postal Inspection Service continues to monitor look-alike advertising and to investigate companies whose advertising appears to be false and misleading or to be in violation of the administrative order, and agreements which concluded our cases. Thank you for the opportunity to appear before this subcommittee. I would be happy to answer any questions. Ms: OAKAR: Thank you; Mr: Nelson: Ms. Young? 8 76 STATEMENT OF RAMS! BATTS YOUNG Dr. YOUNG. My name is Bambi Batts Young. I hold a- doctorate in biochemistry and I'm director of the environment and behavior program at the Center for Science in the PublicInterest.___The center is a nonprofit consumer organization with about 30,000 member§ Who are strongly committed to improving nationaldi, etary_and health policies; The center is joined in its testimony today by the National Women's Health Network which is the largest women's health organization in the United States. Congresswoman Oakar, members of the subcommittee, we very much appreciate the opportunity today to voice our concerns about over-the-counter products, diet products, that contain PPA; Now, theproducts are unsafe for many of the people who take them, at any age, but certainly the greatestburden of risk would fall upon the elderly. We are therefore pleased that the committee; subcommittee; has taken the lead in bringing this problem up for a full and public hearing: Our interest in this drug dates backto 1981. when a review of the medical literature and of FDA files convinced us- that PPA-based pills are potentially dangerous for two reasons. Fir§t, they have a tendency to raise blood pressure in a substantial number of the people Who use them. Second,they do have some stimulant properties that have led to widespread abuse problems among young people and may contribute, as well, to discomfort and behavioral problems even among people who take them as recommended; We also noted in 1981 that advertising for the over-the-counter diet pills containing PPA was grossly misleading, using tacticsthat had been ruled unacceptable by the Federal Trade Commission and the courts during the 1970's. Accordingly, in the fall of 1981, the Center for Science filed 6-= what's going on? aixAii. Well, we might_be having some votes butit's all right. Ja? ti hewn: Keep going on; Dr: vr,. , that's imnortant. Ms, we don't think it's a vote, so justcontinue. Dr. :trot.. da. the fall of 1981 the cente:- filed _a petition with the Federal Trace Commission asking for action againSt the misleading advertisements. Ir. addition, we then wrote to Commissioner Hayes of the Food and Drug Administration urging the agency toconduct an accelerated review of these productswiih an eye toward ban- ning them from the over- the - counter market. Since that time, we have continued to press bothagencies for better regulatory controls over PPA-based diet pills.This spring the Federal Trade Commission issued an extremelylimited warning about the deceptive ads. The FDA says it's stillreviewing the data. We too have reviewed all the safety aneffectiveness data that have been submitted to agencies by either the diet pillmanufactur- ers or other interested parties. The morewe've seen, the greater our concern has grown. 77 Our concern rises from several sources.For one thing, we have Seen a growing number of people likethe witnesses thatyou saw earlier, who report that they'veexperienced severe, Sometimes life- threatening, attacks following theingestion of ..ither a single or,at most, a double dose of PPA-normaluse, not abuse. You've seen some Of them; Othersare reporteci in the medical literature. Close to two dozencases of seriousilamage have been re.g= istered with our hazard clearinghousefor PPA diet pills,as well as hundreds of reports of milder; butstill distressing; Symptoms, and the Food and Drug Administrationin its adverse reaction reports also includes some examples. There's a common strain ofsymptoms that runs through all of these reports, which is whatyou might expect if you had a drug that stimulated the heart and thebrain, What comes up time after time is a racing feeling;a severe headache, bloodpressure rises, and, in 0:ctreme cases, stroke,seizures, and mental diSturbances. Now; I know we've -heard thatthese are just anecdotes, they're Stories, and in fact; you can'tprove that the damage these people suffered was caused by the PPA.That's true in many human health hazards. There'sno clear proof But I would caution youto remember that that's precisely whatwas said a few years back about the thalidimide babies; and itwas said for several years; Nevertheless, the defects suffered bythose babies were very real, very tragic; and as we later found out, verymuch due to thalidimide. You can't just ignore thesepeople, particularly when their symptoms fit with the scientific evidence;and they do. However; the human stories don'tstand alone. They simply serve to back up the weight of the scientificevidence that has been accu- mulating over the past fewyears; One way to look at the evidenceis to ask what is the drug's structure; what other drugs is it relatedto what do they do? Phenylpropanolamine is almost identicalto amphetamines in structure. It's in the same chemical family.It is not as strong. I don't want to imply that. It isa weaker cousin of amphetamine: The chemical class that it fits in hasgeneral properties of raising the heart rate, speeding itup, altering muscle tone in the blood vessels, and stimulating the brain. The medical community generallyrecognizes that though PPA weaker, it does share inmany of these properties and, therefore, i recommendes that people who have suchdiSorders as hypertension. heart disease, diabetes,or thyroid disease, should not take PPA at all; or- if they do so, should do it onlyunder the supervision of a physician. The question then rises, howmany of the people Who are likely to take diet pills suffer fromone or more of those conditions? The answer IS Probably most of them. 1.;et'S just look at the people whohave hypertension. In the American Adult population at large,you have a 20-percent hyper; tension rate. -But people whoare overweight haVe a far greater probability of developing hypertensionto times greater. the tune of 1% to 4 That means; if you do the calculations,that roughly a third of the overweight people generally havedefinite hypertension. Many

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1 11, ! t 04.0 1 ol .1 ti Ili #.4,11 ;L 1 ,1 1,1 79 Ms. ()AKAR.Are we getting close t6 Wrapping getting a little long. it up? Because it's Dr. Yo_uNG. It won't take tad king. I just want to show8-eit116 curves. Thank you. _ _There is a clear ---- on_ dr_day compared_ to days dummy pills. Now that's only abouteight_pointS. You say that'sriot so big. But that's on the average.If the average__ itiereaSeS eight_points there are some people whogo up a wholelot more, and that'swhat happens. This is a youngman who -was 26 years old._ His diastolic blood pressure-T-that's__thelower number in the bloodpressure readingwent up by 36 pointsin response to the drug, 36points, Another youngwoman; a 23-year-old woman, startedout with a verylow blood_pressure,aroUnda_90 over 60, but went up to over 90 when she was taking_ the drug. That's 146 crease in the top number systolic about a 55-point in increase in the botton numberdiastolicpressute=l-and abOUta 30-some All in_ all, in this study, emit pressure. -of the ihdiViduals had--increases t hit took them_ into the .definite_hypertensive range. _Theseare peopi, starterl out with hlbodpressure that is so low that it _represeot:itive of the Ai-net-lean much the population at large, You're talking about, this JohnsHopkins study? what I'm talking ,about. OAKAt(. It's not your_ study; it'sanother study, their study. ovl)triir,11:::!1,1:44;.;1)1I)tc;_sv r-,t Whitt I'm_ sayingisif you iii} of Iles tot. may not see much but if you look tlifiertnees y ad thin I° per-cent. of thatHopkins population expetented extremelyah)ining IllerVaSeti in bloodpres7 _when theywere giventhe drug, not when they i;i0 the ihnunly And tItt-S ww starling out, withIIpottitlittititi of ex- I flock' litiii1(1)-V 1/4.01)14' With very liiw 11100(1-MS8tIre Pic ',film. %%.1ti .404.11 M (ht. tint( t ch.' ird hi littl ht.) 1)r.Woire Nii%% I think 11..1 rill Ii) 111114011e iillY 1.splisibit4 phy- hdoilr ,Vila) 11114 liyotriviision, which these did 11ii1, ,1.10 to 1,11iltni; heel) leile;111411V deniontilr(Ited toilium) n it ;!1,1,1011, :'4) he contiideed nu) iho 14..,1)011,1114, AllIlti10,'111,11'1i 110 171114. III4.11 pilbtine ,1111.11it111,11' II11 101'i 11,11t111 1` 111 t "I. II' /1"111): h'1". Iii hiltI. viir't-j+11li I" hill , Wt 14 Ir;Ithiii 1 111111111111 11111

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I 1 1 t4., ttI 701 t 1,% NI;Sonii 1 _IIt I to ill 111 \ I.( tt .111,.N leripond to 'Awl 14111111Ilhont the it, 1111.114 '4'iII %\ 111101. (s,hi flint I tt.1% i I I ' 11110111'II1110111 11,1 i 'Oil (OE the otroi :111ttlii% -1111111 11111 1,1114'1 (%% :iiiiilbthi.4.,111/1111#11ild Mitt 80 quate scientifically. There was one that did have adummy pill in there. The _power of suggestion is enormously powerful inweight loss and you've got to have a comparison between thedrug and a dummy. I believe in the case where there was a_dummy the average weight loss was about a third of a pound a week : when you took the drug than when you took_ the dummy pill;.,third of a pound over 6 weeks. _Do you really think that the average consumer; if informed; that he or shemight lose a third of a pound a week for 6 weeks, would consider that effective? Mr.VORTLEY; If you're asking me; I'd say no. Dr. YOUNG. Right. Ms. OAKAR. Ms. Ferraro; you have one? Ms. FERRARO. I do just have one question of Mr.Nelson and That was on the charts that you had uphere; Unfortunately, I couldn't see them. They're a little bit too far away.You were talking about look alikes. Mr. NELSON. Yes, that's right: - Ms; _FERRARO: What are they being sold as, cheapertf::-.1 the brand labels? Are they sold as_generics? Is that what itis? Mr. NELSON. Well; I think they're being sold as animpersonation of- the true controlled substance; of abuse-potentialdrugs that -are schedule I controlled substances. They are designed tolook just like the hard drugs that you would get. That's why theycall them look alikes:_ Ms. FERRARO. Oh. But they are not controlledsubstances? Mr. NELSON. That's right. Ms._ FERRARO. That's a good news and a bad news typeof thing. Thank God they're not controlled substances going tothe kids, but by the same token, the kids think that they regetting controlled substances. Is that it? Mr. NELSON. That's true: Ms. FERRARO; How ('we go after those peoplewho arc cleverly using the credit card the parcel post and all that stuff instead of the mails? Mr. NELSON. UPS% Ms. FE/II:AA-10. Yes. Mr: NELSON. _There's no nay the PostalService car go after them; as such. It would have to L.:arie other agency; I suppose the FBI or FDA, maybe FM; Ms. FERRARO, That's interesting. Thank you.I'd like to see_ those charts up a little '.loser, if I might; while theother people are asking questions. Ms. OAKAR. Thank you, Congresswoman. Mr. Wortley? Mr. WORTLEY. Madam Chairman, just to setthe record straight-, I think Dr. Young was referring to somethingelse; It's apparently not the same study :hat I waPworking from. In th:s stody it says that in each of the three stuc. -3 patients wererandomly assigned to groups which --ere essentiallyhomogenous in terms of entrance criteriaEach experimental group received either aplacebo or PEA.--I think talking about two different studies. 81 Dr. YOUNG. It's pt.isible; althoughmy understat .; was that there were two studies which involveda comparison PPA with a Prescription anorectic, rather than with placebo. MS. OAKAR. Mr. Bilirakis? Mr. BILIRAKIS: Madam Chairman, thankyou. I have problems with that name too, ma'am. Justone quick question. How great is this a problem among the airing? That's this committee'sconcern. HOw great is it a problem among the aging? Dr. YOUNG. That's how hypertensiongoes up when you get older. Hypertension is an enormously important problem forthe elderly; particularly. And the point is that it's silent. Ifyou have hypertension you don't necessarily know thatyou have itit doesn't, have any symptoms; And yet it is the major cause of stroke,new cardiovascular diSeases of all sorts in older people: Mr. BILIRAKIS. Yes, I thankyou. I appreciate that: But what I wonder is how many of the agedare using these diet fOr instance, and these drugs that contain PPA? Dr; YOUNG. Well, the best _figureImean, I think the best person to ask here is Dr: Charles Winick, who is somewhere in the audience. Mr. BILIRAKIS-_ Yes. Did he have to leave? Dr. YOUNG. Well, no, he hasn't given his presentationyet. Mr. BILIRAKIS. OK. Dr. YOUNG: I do know -that in a presentation hegave to the FDA in 1977, it was reported that abouta quarter of the users were either -under 17 or over 49. People under 17 aren'tsupposed to take PPA-diet pills at all; according to the packagelabels. And people over 49 are at great risk. Since there are 10 million people total taking thesethings, a quarter of that is 21/2 million people. That is nota minor number of people. Ms. OAKAR. Could I ri .:pond to that point? Mr. BILIRAKIS. I'll defer, yes. Ms. OAKAR. Of the 10,000 indiViduals in 1year who have notified the poison center; which is under the auspices of FDA, whatyou're referring to, Geri, what is their monitoring; three-fourths ofthem were over 50: In addition, they had 1,000 individual emergency cases; and that's their eulmate annuallyacross the country. In addition to that, _I have already submitted this forthe record: There are over 1,000 individuals who have reportedprObleriiS with PPA prescription diet pills anda third of them are over 55. So, it is a- problem that cuts across age barriers. But it certainlyconcerns older Americans. I just have one quick question andone point to make; In your testimony; Mr. Nelson; you were talking about the mail, whichis your jtiriSdiOtion. Probably we haven't given the Post Officeas much authority as you'd like. But nonetheless, I notkedin the chart that one of the ads was a legal stimulant. Committeestaff pointed out to me that the same ingredients inmost of the drugs that you -have shown in your study, that you have subinitted to the Staff and our committ. .w some time ago;are the same ingredients as the over-the-counter drugs. Iu addition to_ this, the State of California'sattorney general went after one Of the manufacturers of diet products: I'mr ,t inter- 82 ested in belaboring whe name it is, unless somebody wants to ask me, because I personally feel that it's a problem with all brands. But they settled out of court because they were using the phrase; "no stimulant;"_and they were asked to remove that They settled, then, with the State of California for thousands and thousands of dollarsforfalseadvertising. So there's a problem, obviously, through the mail and otherwise. [Material submitted by Representative Dakar follows:] THOMPSON MEDICAL COMPANYi INC, 919THIRO AVENUE NEW YORK N.V 10022 (212) 68b.:420

February 10, 1983

Richerd Brungard Deputy District Attorney County of Ventura State of California Hall of Justice 800. Eouch-Victoria Avenue Ventura; CALIF; 93009

Re: Letter Agreement Between Thcm, + Mio:zal Comnan:, t,nd rl Ventura Coun:y District At:crney's 01;_iee

Dear Mr. Brungard;

YOU and -I haVe discussed Thompson Medical_C 4any'a aAveitisins, of weight_controI rroducts extensively, and 'eve reached c,rcaln agreements whit" lifter will memorialize.

With regard to all products manufactured_;_sold et advertised by Thompson_MediCaI Company for appetitecontrol which_contaln phenvlpropanolamine hydrodhIoride, our forth to voluntarily: company has agreed henro_

reference to the safety o: thedrug_ifiits print advertising_ unless a statement like '.he following is given "Before starting this or_env_didt, consult your physician if have aiy underlying health you coldicion such I., heart diSease hyperc,ms$4n." or

- 2. 'Make no reference_to the drug-being approved by a Vetted States Go "ernment advisorv_paneL_or siMV.ar language, in any_print adv rtiaing or packaging until a Lew_HZ.hogreph_ir publisheuor_released. (This restriction refers specifically co-the monograph recommende.:_f: the AchiisOry Review' Panelon OTC Miscellaneous Internal DrugProduCta pubIlShod in the Federal Register. volume 37,number 39, Friday; FObrnary 26.1962).

3. Make no reference_to the drugcontaining "no stimulants" in advertising or packaging.

Thompson (e,,i,al_COMpany agreesto begin immediately to_impIO:,:nc abide by the advertisi4Land_labiling requirements set forth in Final J.,dgmeni: Pursuant to_Sci,ulatien._And this Lettereof Agree 77A, With_respect to labeling modificscion_i_Thempson anticipates it may require severzl Medical Company of packiging,__All_beekaging monchsto_exheusc current invent:-': sent to the S:ace of California will CeMPI with chose agreements within ;4) months. This Letter_of_Atrvement can bs modified by written agreement between Thompson Medical Company and r7,e Ventura County District Attorney's UffIc.. If no agreement can b, reached, the dispute shall be resolved by an arbitrator agreed on by borh parties._ If_no arbitrator can be agreed upon ,ithin (50) days of written request, tes the Presiding Judge of the .5..17,rior o: Ventura County shall appoint an arbitrator to resol'..e the dispute.

This Letter of Agreement shall remain in effect for a period of thrte years.

Please signify your approval -of -these agreements by signing a ropy of this letter at the place indicated below and returning copy to me.

It has been, indeed,_, ple:,surs meeting- with you_ahe_I_personAlIy wiSh you the beta. I sincerely appreciate the insights you s'ared with us.

Very truly yours,

THIXWBOX MEDICAL COMPANY, INC.

SDAifj Si_Daniel_Abraham Chairman of the Board

AGREED

6,4 7 7,44,11C42 Richard Brunpard 85 Ms. OAKAR, Bambi; L want to thankyou for the fine work that you and the Women's Center have done in thisarea Its a thank= less job. I know you've run up against all kindsof brick walls and harassments and everything else. But I thinkthe work doing is just tremendous and thankyou both very; very much. Our next panel is Dr. Sorrel Schwartz withthe department of pharmacology, Georgetown _University School ofMedicine, Dr. James Rainey, private practive of endocrinologyand metabolism, Dr. Thaddeus Prout; associate professor of medicine-at Johns Hop- kins and chief of medicine at Greater BaltimoreMedical Center, and Dr. Shirley Mueller, who is the di::beter ofneurology; Regan- streif Health Center; Indiana University School OfMedicine; In- dianapolis, Ind. We want to thank you all for coming. We knowYou're recognized in your field and well published; and thank you so much for being here. Dr. Schwartz; could we begin withyou. Can you make your remarks somewhat brief so thatwe can get to ql.estioris? PANEL :3 MEDICAL. _EXPERTS; CONSISTINGOF DR. SORELL SCHWARTZ, PROFESSOR _OF PHARMACOLOGY;GEORGETOWN UNIVERSITY SCHOOL OF MEDICINE,_WASHINGTON; D.C.;DR, SHIRLEY MUELLER, DIRECTOR OF NEUROLOC.;Y,REGANSTREIF HEALTH CENTER; INDIANA UNIVERSITY SCHOOLOF IVIEDI- CIINE, INDIANAPOLIS; IND.; DR THADDEUS PROUT,ASSOCIATE PROFESSOR _OF MEDICINE, JOHNS HOPKINSUNIVERSITY SCHOOL OF MEDICINE, AND CHIEF OF MEDICINE,GREATER BALTIMORE MEDICAL CENTER_,_ BALTIMORE, MD.;AND DR; JAMES RAMEY, ASSOCIATE CLP:iCAL PROFESSORAT GEORGE WASHINGTON UNIVERSITY STATEMENT OF DR. SORELL SCHWARTZ Dr, SCHWARTZ. Thank you, Madam Chairman. My comments have been submitted in writing tost Submit them for the record; and in. the interest of tin peating them. I would just like to highlight twoor three Ms. DAKAR Without objeaion. Dr. SCHWARTZ. The first is thatone of the most important as= pects of evaluating the safety and efficacy of a drugare the phar= m2cokinetics. This is determining the absorptiorA, diStribution, and flirnintition of a drug. Toxicologieally this isimportant from the vim point of possible accumulation of the drug in the body. Today there are no standard procedures recommendedfor animal studies_ or otherwise by the Food and DrugAdministration vhich regaire _that pharmacokinctic studies associatedW(P-% age be performed. This is extremely important becausewe know that the eldely adult has changes in renal function, in hirer function;in the volume of water in the body; in the amount of fat inthe body, that all impact upon this. I would also like to point out that the difference betweenan efficacious over-the-counter drug and a prescription drug is inthe therapeutic range. That is, the difference betWeen the effective dose and the toxic dose. 9 86

fit' ie over-the-count: "1g, the C.errif.mutic range is wide so tha .1i is a leeway for,tien error taking the drug without ial_superyision. nnot be assured; ;.her? any re:iSnci 'o 1j-lieve, that the rapeutic ianges stolloger anti middle _aged atitu ipplyto the elderly. So; th.__t afety of oye..-the-cold_.,-.ter drugs in th:Wetly adult based on experience in the, yetu.ger pop:mi.:ion is not particularly_assu. rird. ThOse are the__points which _).L;i! to _highlight froth the viewpoint of where I think there might lie regulatoryilids,-ot cen- tai:.ly encouraging -of- regulato, needs. I will sayin passing That I worked with the Postal Servix on_this matterifound the PoStal Service to be extremely dedicat,..3d. Thatwasfortunate because we also found a great deal of difficulty early on ingetting any coopera- tion at all from the Food and DrugAdniirtistration. Thank you. [The prepared statement of Dr. Schwart-.follows]

PREPARE:, STATEMENT OF SORELL L.SCHWARTZ, PI!. D., PROFESSOR OF PHARMACOL- OGY,- GEORGETOWN UNIVERSITYSCHJOL OF MEDICINE, AND SCIENTIFIC DIRECTOR OF THE CENTER FOR ENVIRONMENTALHEALTH AND HUMAN TOXICOLOGY Mr. Chairman, my name is Sorell LSthwartt-I am Professor of Pharmacology_at Georgetown _University School of Medicine andScientific, Director of the Center for Environmental Health and Human Toxicology. I hold aPh: D. in Pharmacology &din the Medical College of Virginia,Virgins Commonwealth University. Since re- c.:;;ting the degree in 1963; my areaateoncentration has been primarily in toxicology. A copy of a CurriculumVitae detailing my educational, research, and ether professional background is appended. It is my understanding that staff wishes me todiscuss_ the matter of advertising and distribution of over-the-counter drugs to the elderlythrough the mails; in_gen7 ert!nd the situation with_phenylpropanolaMine, in particularThis shall be my task it I Prst wish to establish the basis for discussionby- introducing a much breeder problem: TIrqt is the lack of any appreciableinformation on the toxicity of drugS in the it represents an alarming gap in ourknowledge and, feithat meter, in our research efforts. The evaluation of any new drug begins with animalstudies. These studies incliide the evaluation of the acute toxicity, subehronic, andchronic toxicity of drugs. They involve_an evaluation of the pharmacokinetite whichgives valuable information on how the drug is absorbed, how it is distributed, andhow it is eliminated; Such infer! mation is necessary to determine whether accumulationof-the drug within the body over a particular dosage schedule islikely tc occur or not. Following animal studies; studies are done in normal adult yolunteers todetermine tolerance levels and again. te determinc pharmacokinetics; These are theso-called Phase I clinical :Arid- ies, Su'..r.equent to this, clinical studies are then done toevaluate the actual efficacY of the drug. These data are thenused to arrive at recenrune_rded dosage regimens and warnings for the use c" the drugs. To ins,knowledge; this evaluation procedure rarely, if ever, takes into account the probietr* ofthe elderly; This is in spite of the fact that changes in kidney function, liver and other factors which inflti Once -the ability of the body to _handlethe drug are known- to be different in the elderlY when compared_ tc young_andmiddle -aged adults. This is in spite of the fact the centre.; nervous th-i. the sensitivities of the various physiological systems, e.g., system, are known to be alteredin the_elderly when compared to young an.' aged tr!.tilts. This is in spite of the fact that the immunesystem, the blood-Wm...rig tissti,., and other physiologic systems which canresponcl_to_give serious and lifa- 0.rr-!atening drug reactions are also known W be acted uponby drugs in the clderly itmrdiner different in young and-Middle-aged adults: One response may 5e that the Fckid andDrug Administration requires chronirt toxicity studies of_ drugs to bvin at or before Well!and to proceed in death of the animal- from old aga witlinal_going into the F,pecific reasons,the way in which theSe studies are done are iradequate to _provide usparticular information -on the effct..,S of drugs in the elderly. An entire_ new setof protocols is required before we can even begin to predictpossible responses in the elderly human from animal SUM- 87

les.I an not suggesting that the elderly become key subjectsfor Phase I clinical studies. On the other hand; drug labeling requirementsaddressed to the needs of the elderly_involving various precautions- inuse of drugs are rare. Untoward responses to drop !'y the elderly are everyday occurrences. Yet they continue to be referred to r.s idiosyncratic responses. Thecommonness of their occurrence belie the use of the word idiosyncrasy. The fact that polypharmacy (multiple drug therapy) isthe rule -with -the elderly compounds problem in geometric proportions. Considering the ill-definednature of drug action in elderly adults along with the dosecompliance problems associated with polypharmacy; only an incurable optimistor a fool would expect an uneventful course of pkerrnacotherapy in an elderly individual. Similarly,_over-the-counter drugs whic,, nave any efficacy cannot be consideredto be toxicologically innocuous. What distinguishes the efficacious over-the-counterdrug from a drug requiring -a prescription is the dosage latitude between therapeuticefficacy and untoward Side effects. Yet, even this assumption cannot be assured in theelderly, especially if that elderly individual is taking prescription drugs in additionto the over-the-counter medication. This should provide a particular prospective withrespect to the use of over-the- counter drugs by the elderly and the encouragement_of thatuse by the mails or any Other advertising techniques. This is ofconcern both with respect to encouraging the elderly to increase the number of medicationsthey are taking, and thereby in- creasing_the compliance problems associated with polypharmacyand with respect to increasing the possibility of drug reaction-or interaction with other drugs. The necessity for the risk benefit evaluation is obvious. Inmanycases, the needs for the potential benefit outweigh the risk& Such is not thecase with phenylpropanolamine (PPA). PPA is a drug which is che.mically_relatedto amphetamine. Amphetamine is known for its ability to stimulate the centralnervous system, as- an appetite suppressant and for its ability to increase bloodpressure. The means by which the amphetamine exerts its effect on blood pressure is to constrictblood vessels. Early studies with PPA suggested that it had little of the effectsof amphetamine and That its major activity is to constrict small blood vessels. Sincethe small blood vessels in the nasal tissues are dilated during nasal congestion; PPA;because it can constrict these small blood vessels, was used as a_nasal decongestantwhen taken orally. It now appears that PPA has a_ much greater likelihood of affecting bloodpressure than originally believed. As early as 1965 and 1966 therewere reports of incidents of transient hypertension following PPA_ ingeStion [1,2]. A seriesof reports froth Australia from _1978 through 1980 13-7] focusedon the problem of PPA-associated hypertension. One report [7] describes studies of the effects of either0 mg. or 85 mg: of PPA in medical students. The high dose causedan increase in blood pressure diagnostically classified as a hypertensiveresponse in 12 of 37 subjects. Hyperten- sive reponses to PPA have now been documentedon numerous eccasiors in this country and other counties [_6, 8]. The elderly are susceptible to changes- in bloodpressure, both those that can result in a reflex hyptensive response and resultant fainting andinjury during feel as well as e cereb:a.,a.scular accident -from the hypertension. Work done by the Center for FsrenSic and Environmental Science at the Universityof Ne -v Mexico School Of Medicine liaS revealed three cicaths associated withintracranial hemorrhage-from the, ingestion of look-alike cbeeei byyoung people Though the- implica- tion of look-alike drugs is that there ..6san abuse invoi,ed, this is not entirely certain: and the idea that PPA could cause a stroke ina young person leads to some frightening concerns about the elderly vis-a-vis the discussionaoove regarding dip= ferences in physiologic sensitivities. PPA is .narketts.-1 through the mails an.' in retail ou:letsas an anorectic agent (appetite suppressant. A panel conveaeu as part of the FDA Ol'C drugreview concluded that PPA ,ff!ctiv-, and safe when used as an aem-ectjt- over-the-counter agent. Notwithstandi that Life ovetwhelniing_majority mc-lical opinion considers the use of anoret tic drugs as an inadequate approach to promoting permanent weight loss in obese indivicivals, there was and still is little (lathto 7.uppoit the con= elusion that PPA is an effective anorectic drug.-More to the point of thisdiscussion, there is the data just described to suggest that PPA is notas safe as the panel imag- ined. Part of the problem is that the is made up of a group of people highly qualified in their particular areas of concern. Unfortunately,none of these areas appear to be concerned with clinical pharmacology and with toxicology.

Footnotes a:. end of article. 88 Testimonials and claims by the manufacturers of PPA containing diet aids notwithstanding; there is no reliable evidence to suggest that PPA is an efficacious anorectic agent: There is a preponderance of evidence to indicate that mishap associated with PPA use by the elderly is a foreseeable possibility. There is just no redeem- ing feature of the over- the- counier diet preparations which 'justifies the potential hazard they present to the elderly population.

REFERENCES L °stern, S. and W._ 11. Dodson. Hypertension following Ornade ingestion.J. Amer . Med. Assoc. 194:472 (1965). 2. Livingston, P.-1-L Transient hypertension and phenyipropanolamine. J.Amer. Med. Assoc. 196:1159 (1966). 3. Frewin, D. B., P. O. Leonello and M. E. Irewm. Hypertension after ingestirr- Trimolets, Med. J. Aust. 2:497 (1978). 4. Horowitz, J. J. J. McNeil, B. Sweet, F. A. O. Mendelsohn and W. J Hypertension and postural hypertension induced by phenylpropanolamine i' lets). Med. J. Aust. 1:175 (1979). 5. King, J.-Hypertension and cerebral hemorrhage after Trimolets ingestion.Med. J. AuSt. 2:258 (1979k 6. Lee, K. Y., L. J. Beilin and R. V n. Severe hypertension after ingestion of an appetite suppressant (phenyl; : .line with indomethacin). Lancet 1:1110 (1979) 7. Horowitz, J. D., L. G. Howes, Ic ,q1`1111idiS, W. J. Lang, M. R. Fennessy, M. J. Rand and W. J. Louis. Hypertei r .:6.es induced by phenylpropanolamine in anorectic and decongestant prep anc_et, 1:60 1198ft 8. Bennett, W. Hazards of the app.. pressant phenylpropanolamine. Lancet 2:42 (1979). MS. °AKAR: Thank you very much. Dr. Mueller? :1.'FATEMENT OF DR. SHIRLEY MUELLER Dr. MUELLER. I am Dr. Shirley Mueller. I am aneurologist. I practice at Indiana University School of Medicine where I'm an associate professor. I'm director of the neurology section at Wisher Memorial Hospital. rill also a member of the National Heart, Lung, and Blood Institute Advisory Committee on Atherosclerosis, Hypertension, and Lipid Metabolism. I am lead author of 11 original papers relating to hypertension: I think that our time would be spent most productively if Iwould develop for you how _I became interested in this problem: About2 years ago I saw a 16-year-old girl who cameinto our emergency room who had a seizure. She relatedthat 20 minutes prior to having this seizure she had taken a look-alike pill; apill made to look like amphetamine; But when we analyzed, it, in real';yit contained phenylpropanolamine, caffeine, and affedrine. After that, we saw 10 more patients in our emergency roomwith similar sorts of problems. Of the 11 patients, two had seizures, four had se-reheadache associated with an elevated_blood pressure; and the rr..mainderhad psychiatric problems. All of these patients_ related havingtaken a look alike pill within an hour before the event, the event being psychiatric problem, the severe headache; or seizure. Ninc. of these patientS had their gastric contents or urina analyzed for presence of drugs, and rhenylpropanolamine andcaffeine were found; So, we're talking aboutMr.Lantos, are jrau coming? I want you to hear this We're talking about not acontrolled study; but a retrospective study here; And we did have an apparent cause and effect; since we were able to identify in the urine orgastric contents the druand the patient relsted to us that they had,

93 89 indeed; taken a drug they calleda led( what was in their gastric and We- analyzed urine contei' F. tound phenylpropanolamine,caffeine;,and relatedto the sympto.ns. NOW, look alike pills are different than diet pills. Look alike pills . a-e immediate release andmany of the diet pills are time release. Immediate releasecan be more dangerous because there will bea rapid elevation in drug_ level. So,the time release could be safer. We were interested in lookingat this probleM Under controlled conditions, -a prospective study. Wave done two things. One isthat we have looked at animalS, and ti'other is that we submitteda grant to the National Insti- tutes of Health to look at the effect human blood pressure. of phenylprepanolamine OAS Let me go over our animal data Wehave looked at hypertensive animals and animals with normalblood pressure. The hypertensive ani:nal that we have looked at isthe animal called the spontaneously hypertensive rat; which is likethe human with a essential hypertension or hypertension ofunknown etiology. In the spontaneously hypertensiverat, when it is administered six times the recommended dosaperweight, the percentage ofcere- bral hetherrhage thatwe note is 18 percent. This markedly different than the hbernotensive animalswhere we do not note_cere- bral hemorrhage. A cerebral hemorrhageis asseciated with an elevation in blood pressure in thesehypertensive anilyials, Now, we're using six times therecommended dose. HoWeVer,we only studied about 2" olithal. Ifwe could expand our study to, let's say; 100 or 200or 400 animals and use the recommended dose; it is possible that we would findan increased incitk-i.L'.0 of cerebral hemorrhage in the nerinotensive animals. Animal research does directly relateto human research_ in that our bodies do not act totally differently from animals.We plan, as I mentioned; in the future to lookat humans and determine the effect of phenylpropanolamine inallowed doses by the FDAon blood preSSUre in humar.s. We havenot yet done that I'd like to talk withyou today about why some individuals suffer niedieal complications related toan elevated blood pressure when hey take diet pills containing PR.IC Iu.:-.!&you may have something that was handed out tcyou It's a summary of what we're going to be talking aboutover the next &vminutes. The most obvious reason is thatthe leactien is peculiar to the individual, t 5 at is, idiosyncratic. Sineemost of the literature telat= log to PPP., complications is anecdotal,this must be considered possibility. a If the ,..eactions rer-ortedare idiosyncratic; these 5ccurrerics cannot be avoided. Then the crucialquestion is bem.cit./risk. If the benefit is high the riskmay be worth the benefit. I someoi e else will direct his testimony to thebenefit The risk may be_hig and_We'll talk about that in pointstwo and three, so that effectir,..t- ly eliniinatei: the posr-,ibility of iuiosyncraticreaction. Anoth"r possibilit explaining the occurrenceof medical comply cations is that consumers ignore the dietmedication package wan- ing,Whith is ii..?roduced below: -You- are familiar With this. been read to you several tines. I won't deit aga;.n. 90

_Sinceconsumers-think that &OP-the-counter drugs aresafe; they often eci not read the package insert: TIlus,at-risk groups, such as people with heart disease, may take the pills onoccasion and suffer complications, The solution to this is that consumereducation should be undertaken -on over-the-counterdrugs so that the public reads and follows the directions. HoWeVer, even with a large effort inthis regard, some People would still ignore the package insert. Thus,again, We are back to benefit/risk ratio. Yet another pa:_3ible explanation forcomplications is that indi= viduals with a normal blood pressure beconieacutely hypertensive when taking the allowed dose, and suffercomplications: StiidieS sponsored by the drug -_:ompanies Themselvessupport an elevation in blood pressure secondary to PPA Dr.Young has already alluded to this when she showed you her graph;and I'd like to slid* you another graph taken from a study sponsoredby a drug company that was submitted to the FDA. Before going_ over this graph I just want to talk alittle bit about the blood pressure studies. They're hard todo. They're not easy to do: A lot of the studies that have beensponsored by the drug -companies, in all probability; have not been doneaccurately. Likewise, a lot of studies done byothers are not done acc,:,-ately. But let's go over some of the reasons that they may notEl:we been done accurately. Our blood pressure varies during_ heday, Sri it's important that the blood pressure is always taken atthe sanr time of day in any individual. Also, in any oneindividual_the block'. pro..,re will be diffetent than in another person. So; the verybe-doily is fid ielate the blood pressure; taking a sugar pill, to the pressure while on the drug. hi other words, my blood pressu,--,-- ,nay run120 over 80, someone else's may run_101) over60: So, eed to compare each of us to ourself on and off the drug. Alio, in order to take blood pressureaccurately, the larst of three blood pressures must be averaged toclet,rtnitie the accurate blood pressure; hi many studies theblood pressure is taken only once; and this leads to an exaggerated highinitial blood pressure: which rtm....s that all of the otherblood pressuteS may be off if allof thPiy: are compared to on early morninginitial blood pressure. an expert must take the bloodpressure because it is very o):(Tzult to do. Someone who has beentrained according to the recommendations of the American HeartAssociation should do it. The study that is shown in thisgit-ph was done according- to some of the criteriawe've _just talked about in terms oftaking blbbd pressure accurately- and doingstudies accurately. In this study; sponsor( d by one of the drugcompanies, the bloon pressure shown on the Vertical axis and the time onthe horizontal axis. The systolic or greater of the twoblobd pressure readings is she wn above, and diastolic or lower of the two blood pressure readings; is snown below. The solidline represents th*, blObd pressure after taking 15milligrams of phenylpropanolamine.The dashed line, after taking_a sugar pill. Although most blood pressure pointsdid not diffe: "netween placebo and PEA; at 4 hours there is awide difference: In some indi- 90 91 viduals the dirty,- ence inpressure between drug and placao would have been far ieater than illustrated here; since this is theaverage of the gro . nd Dr. Young, I think, presentedsome examples to you. Since rapid, dramatic increases in bloodpressure can lead to headaches; seizures, stroke, and death, -it is possiblethat in a group Of several thousand people, rather than the5d studied here, that such a reaction could occur. In addition,a number of people have a mild, periodic; asymptomatic, elevation inblood pressure when taking PPA, as demonstrated in the graph. Although the concept of periodic elevations in bloodpressure can lead to sustained hypertension is controversial,there is evidence to support that concept. This would mean that periodicelevatibnS of blood pressure secondary to PPA could,over time; cause damage to body organs that may lead to permanentdamage. In order to settle these questions,a cardiovascular review committee, expert in the physiologic effect ofperiodic elevations of blood pressure on the body, shouldexam the existing data on PPA-containing drugs in order to opinion on its safety. In addition, some individu- p 41.. be (ce:zsately sensitive to the interaction of commonly us= and PPA.FrJ Aexample hypertensive crises have been rev. ,n individuals on indomethacin, an- aspirin-like compound, who took PPA-containing drugs. Indomethacin is not listed as a contraindicated drugto take with PPA on the package insert. Thus; animal researchis needed to de= terrnine what interaction, if any,can occur between PPA and indomethacin. Indomethacin has been shown to enhance bloodpressure elevation in the presence of another drug similarto PPA, se a precedent for such-re-search has been substantiated. Another explanation for complications is thatan at-risk group, not covered in the package warning; take the pills andsubsequent= ly have complications. One assumption made withthe package warning is that everyone with high bloodpressure is aware of his condition. We knov, that one-half of the_23 millionAmericans that have hypertension are not aware of it. So,a large potential at-risk group exists; In addition, since hypertension ismore common among over weight individuals and overweight individualsare more likEly -to consume diet pills, the at-risk D-ot.p is even larger than would be expected. Women on birth control pillsmay be at special_riSk_be, cause they:gain weight while on the pills and thereforeare susceptible to taking diet pills. At the same time, significant increases in diastolic andsystolic pressure occur in these women. MS; DAKAR: Doct.z, could you summarizeso that we can get to some questions? Dr. MUELLER. I'd be delighted to dc so, These at-risk groups need to be studied under normal enviro,m- Mental conditions. Let me explain that toyou. The s4, have been done so far, sponsored by the manufacturers study the people- while they are eating, for the roostpt.; not allowed to (Innk caffein... drinks; We know thatc;=.,

92 Vates blood pressure independently, that caffeine iscontained along With PPE in many diet pills. In addition to that; people aren't allowed to smoke. Smokingis a normal environmental condition as well. Smoking canelevate blood pressure. So, we need to study people with normal blood pres- Stire in the at-risk group that areexposed to the diet pills, plus normal environmental conditions. If this were done, Ithink an even more dramatic rise would be noted than our graphs. [The prepared statement of Dr. Mueller follows:] 93

PREPARED STATEMENT OF SHIRLEY MUELLER, M D., DIRECTOR OF NEUROLOGY,

REGANSTREIF HEALTH CENTER; INDIANA UNIVERSITY SCHOOLOF MED-

ICINE. INDIANAPOLIS. P;7..

Lt.t 1,, :o ,:;cri,ncc rhenylprcpanol.:Mine

(PPA) anc PPAIrLftcin.l. Eleven patients were scvnIAour eLerE.eney rocm

.1711 sy...p1LM5,huu4,1C1.1..5and 5rizercs rLlared tc ingc;tion cf

PPA-ecntJin. pills. "Lcok-alikc. rill; are made tc Icck

Lr.pnet":in:J;Lutin ruzlity contain PPA, caffeine anc se;.etimas rrnecrine. ThuFaticnT5ere described below. This chart vas tc%en from P'ueller, SM. Neurologic CcL.plications cf Phenylpropcnolamine Use.

ct Phrnylprcpcnolal.ine (PPP) "Look-AMA:" Pills

Drug analysis 1.1 Age Ilietnry plus physiral exam

Tuui, PPA plus unidentified substance 1 5 ea 6 pink Cali thought to be "speed' one hour later, de, eloped in urine htndnh. And was tremulous

M 37 Took Ina 'lilts or speed," on hour later, rrA in urine do elis.ed ie.-re headache and %olmted ITA in urine 3 N1 72 Tick II. ell.irk lwatost e,7 three:hours late: .4.1e1,1.1ined or it rare headache: ECG abnormal PP.; plus caffeine in urine 4 M 21 Tool. tun "black beautics."_headathe, 171.11107, diaphoresis, end muses plus omit.: (talond. pupils 'sere 6 S and poorly reactive PPA and cfreine.plus unidentified 5 F 19 Took "pink ladies" end 15 "speckled pups" thought to be "speed: ontlult ho,_later. substances in urine din elop.d A hesd3she. diaphoresis. and cmiting. ECG abnormal PPA in urine 6 M 29 Took at lcut_two_lalack_boauties7 and smoked two pints. tegan acting in a ticarre_fachion. including undressing a the airport PM in urine 7 F n o.....R...amo,.....h.eva.mle wysitok,e1.4e.eirrpe,ed ertehrenic undirretentiated thimphrtni rolloned ITA in mine A 13 MI, u;:, rl .1114, by hanging FrA in urine 9 F 7 Tick i .1,11.1.,c1.144tun." rnd fill. c. d %iii.1. oat The .gitkrntup" tontained fAcmg nt. it, F 17 Tent .o -pia r,t .uh7 _bill bilis %id to be re.; ,,:. -.,,,In cm, mnotes :ale, C.P.A_niZerig 4( caffene. and 25 rig of r,erl.ephedrtne

The 'diet pill"contained PPA,_212ffrng F 27 'reek d :11" telit,td to contain '1;41 dA- r, r er.I.,r1 etdre ns noted °Nor..., and 25 mg of ephedrine 111 ...... )...

BEST CON AVA11411

CI 27-436 0 - 84 - 7 94

L; i,nlycIL Gastric contents cr urine were analyzed by thin-layer .rn., in niNe p.tiunts. Positive findints were eopfirmec Cy ces Phcnyliropanclamire was icentifiee in cach_cuLe. _In two . c.ttinv ee5 dlho found; dne an unicentifiee staStence eas e intw.. others. This perlicelar druc screen rules out core than es c!.ible components ofthe sebstance being znalyzed-Wenneth hi.ector, Chemical Futhclizorisherd Memorial HopsItal, .n Inel.na._pereunal co:,0uhieatien). ho am[netamines were

t ,e. two p.t icots ,itli suiZerc.L,r6; ch,,atce,raphy analysis of caffsind and I 1 ,c,1 to those inrjestee .hosed , ,Itropa

rive patients with headache, blood pressure was elevated for

(27 years, (mean SE?:). The arturi41 pressure was

4 Inc (ne;:n s SE) with the averacc for arc being

potients vomitoc enc. leo were Trsnulous. Teo

I. tr abnormalities. All of these

aLn.r, r,sulveu 'ter afew moos in 111c cu.crscncy room or aft.r

n tn,

It N!,! to PPA the c.ese of the sy,ploms of the .r iced since nrn, h.d ..speriene,d previous cimilar episodes,

.1I h.c 1,1 r BOA n the prcc,. in, hours,lane cuniud Glhcr ereLs) cnc

must oil, rrSi.c that could 5dU5., such syrpTc,s wer absent from Urine and

Ns.tric Ferlhermorc, the ceerso of sy:..plees wes ccmpetitle with a ere, recvtion.

Altheu;11 of thg patient_ rep-,rted in this study' had taken more than the allowno .eznity it emn or PPAr:affeine, the symptoms that

reselted illustrate .r..liewtiens that can occur cocondery to FPA or

FPA/caffain.. Tne major ciffe.enoe Effween the "look-41.W pilis and

'din.t iS rho termer eften .rein :LI, immediate release form where roc n.ajerity of the FPA anc °PA/caffelne t;et preparations are in a tine

TI of fuel of tOe "foue-alike. bills may be more

, ,Id n,1 i. cf ;iet. ciftel. ,uulo

likely to otter. 95

rdve performed animal studiet whiCh indie4te that hypertensive

are Lora susceptible to brair hemorrhage attar six times thu allowed -.:0/weight (FO/. stendardS) of PPA/Caffeine administration than enir:..31s kith a normal blood pressure. Thu presence cf brain hemorrhage was uct,rmirea bya neuropathologist in blinded fashion using histoloolc technic,..cs. 'ne can conjecture that hypertensive humans are also

risk" worn rrA/ *faint:. Since a large percentage of cur hypertensive ;i, s not aware that they have hypertension and since

1.i.;.,rIttl..i,A1 i , r, .1t,r1 n nr, cv,r,(21.7h1 individL.1 Is susceptible to

TkkinE (jut pil -,1 rIbl." group islarge are rot' readily

icentifioblu. In subjoct variability wuulc potentially make

5CLO people more susceptible 10 Co,dplirctiOnS from allowed elobet of PPA/caffeine then others. 96 Ms. OAKAR. Thank you very much, Dr. Mueller.Dr. Prout? STATEMENT OF DR. THADDEUS E; PROUT Dr. PROUT. Thank you. I'm Thaddeus E. Prout, associateprofes- sor of medicine at theJohns Hopkins University School of Medi- cine and chairman of the Department ofMedicine at the Greater Baltimore Medical Center. rye also been madechairman of the Pharmacy and Therapeutics Committee of the AmericanSociety of Internal Medicine. I'm a fellow of the College ofClinical Pharma- cology and presently president of the Socy for Clinical Trials, whose sole purpose is to maintain the integrity ofgood scientific Work. I might also say that I should put in two disclaimers.One would be that I didn't have anything to do withthat last study that was purpcirted to come from the Hopkins. I also talked to themabout it and argued with them about aVeraging their data andthereby nul- lifying some important results. The other is that I speak for myself today and not for thesesoci- eties of which I am a part-- I wanted to remind Mr. Pepper before he leftthat I have also. just been appointed to the planning andevaluation task force of the National Council on Patient Inforination andEducation, which is one of her favorite committees. A great deal has been said this morning; andI wish to use my Spare minutes as others have byresponding to some of the comments already made, and submit mywritten testimony for the record. Ms. OAKAR. Without objection Dr. PROM'. no stranger to this controversy.I've been at it; longer than most here, for some 15 or 20 years.My most recent involvement has keen in association with the attorneygeneral's office of MarYland, when a company from yourfavorite State; Ms. °akar, had the temerity to come intoMaryland and give false advertising. We went at them and won. Ms. OAKAR. Great. Dr. PROUT. The important thing, however, isthat this is very wasteful of time, as the respondents for the FDAand for the Postal Service, and others, have shown. You needonly to change the name of the company and changethe name of the drug and you can be back the next morning atsunrise with the same product under a different label. It's that simple tocircumvent the proceSS. I think we are going to have to look at theprobletri, as you have said, in a general Way, and try to find a meansby which the whole PPA industry can be attacked generically. The question of anecdote and risk/benefit has come uprepeated- ly. Anecdote is, I suppose, a way ofintroducing the concept that if the numbers are small enough, theydon't matter. I know that the users of that term woulddecry that interpretation, but the fact of the matter is that it's difficult to givemathematical significance to small numbers when there is a largeunaccounted denominator. We all remember when the problemof strokes in young women taking the pill WAS an anecdote, and it took some verysophisticat- ed epidemiologic studies to nail that onedown. There's no way to

1 0 t 97 run a controlled clinical trial on the side effects related to PPA. Indeed, I personally do not feel that it would be entirely ethical to do a long-term study in this field; knowing the problems as we do. I think that we need to deal with this in terms of risk/benefit ratio because I think we've established, through the dialog between Mr. Wortley rind Dr. Young from the Center for Science in the Public Interest, that the trivial degree of weight reduction that can be expected from the use of these pills, could not really be called effective, and over a lifetime of obesity the loss of a temporary quarter or a third of 1 pound, after 6 weeks of therapy, is hardly "effective therapy." I make that point strenuously because in talking about a risk/ benefit ratio, if there is no benefit, then no risk is warranted, none whatsoever. It is an x over zero and the risks mathematically, is infinite and in the practical world of medicine is just not acceptable. I would like now to talk about what is wrong with what has been reported to come from the ad hoc committee of the FDA on PPA: First; their decision concerning the safety of PPA came from the safety review that was actually done concerning the short-term use of these pills for their decongestant effect. They did not look, at safety themselves; except to review other data very quickly, and to go on to the question of efficacy. They then accepted as efficacious a "statistical difference" as describes in the studies that were prof- fered by the producers of these pills, the authenticity of which, again, I think we always have to bring into question. What we found between 1972 and 1974, when I was chairman for the FDA of a conmmittee looking at the effect of amphetamines on weight reduction, was that the best foot that industry could put forward was none too good. The FDA looked at over a thousand studies; volume after volume: We_then came down to 200 controlled clinical trials that were worthy of scrutiny. Here we again came up with the same trivial evidence that the difference in weight loss was much less than 1 pound per_ week averaged out over the studies which were only 6 to 8 to 12 weeks duration. One cannot call this effective weight reduction. We also found evidence of the lack of safety, and on this basis, we first recommended that all drugs with abuse potential be scheduled as dangerous drugs. When FDA failed to act on this recommendation; we agreed that obesity should be taken away as an indication for the use of amphetamines. We had already won the fight in Maryland and this had already been done there as well as in Canada by the time the FDA got around to accepting this final recommendation. That act by the FDA essentially stopped the traf- ficin amphetamines as a weight-reducing excuse for proffering these over the signatures of reputable physicians. So much for the moment for the risk/benefit ratio and the evidence of efficacy. I'd like to go on quickly with the remaining time to simply talk about safety and, once again;_the word anecdote comes up. I don't think we can laugh off the Horowitz Study from Australia that showed that 30 percent of the people who were young and healthy came up with a significant and dangerous increase in the diastolic blood pressure. 14 98 I also think that the evidence from the Hopkins; when it's looked more seriously, shows that there are a numberof people in that study as well that had significant hypertension; So these are not just unusual samples they confirm the danger. A third of the young people who take this drug in the recommended therapeutic dose; have dangerous elevations of their dia, stolic pressure. That is no longer anecdote. This relates to the known physiology of these drugs, which Dr; Schwartz could describe much better than L This known physiology fits in With all of the side effect§ that Are are now reported as happening to people using these drugs. My own scientific evidence is also a bit anecdotal in the sense that a former resident physician who found himself interested in going into -a remote- area; and I apologize to any people, here who are from North Dakota, if I offend them, buthe went out into Fargo, N. Dak., to set up practice; There, in the course of 6 months, he found seven people in his accident room that had severe an', phetaminelike effectS from PPA. Now, is that anecdote? No. Dr. Albert Dietz_ published this in the Journal of American Medi- cal Association. It's a well-known study and it's a respected study. And how do you think that an over-the-counter drug became this product of abuse in Fargo; N. Dak.? Certainly it didn't take a large drug push to get it out there. That came about by real anecdote. Any high school child knows that if you take enough of these drugs you can gei. a high; and seven of them appearedin Al Dietz' accident room in a 7-month period. I think that's a little beyond scientific anecdote and I'd like to call the panel's close attention to it. We are also saying that this has to be looked at in terms of the aging population; To the aged; I think all of us will agree, youth _is beautiful, slim is youthful, and that they are interested in weight reduction is an axiom. You have some information; Ms; Oakar, that shows that they are; in fact, using these drugs. They will continue to use them. They will continue to use them as long as they are advertised for the reduction of weight; They are ineffective and the risk is unacceptable and untenable. I think that what we are watching here -is what I might call the all-American over-the-counter flim-flam. They are promised thing like is "Take out your savings and buy our drugs and we will make you youthful and young and slim again." This is a fraud and it should be dealt with as a fraud. I don't believe that we are talking, as Mr. Lantos has asked us not to talk; about withdrawing these medicines, from all over-the-counter use. However, I do think he would agree that if his family and his young relatives are using ineffective _drugsfor -the- wrong reason, they should be taken off the market for that indication so that his familY can save their money. I think we can now look to the indica, tions for use of these medicines and whether they should or should not be allowed to be used for obesity. I would say thenthat we may have two additional actions to take: One make them prescription drugs, if they are _to be used for obesity. TVvo, make thenischedule 2 drugs. Here I differentiate to man schedule 2 of the Dangerous Drug Act, not the categories of the FDA that have been bantered about; Schedule 2 means that a doctor has to write the prescrip- 99 tion. ile can't renew it over the phone. Itis controlled. These should be controlled substances; and; momentarily to return to a previous comment. Ms. Ferraro was not too far off when she said; "There's good news arid bad news." Indeed, maybe, "there is bad news and bad news:" These drugsare not called controlled drugs; but they should be when we look at the experience around the world in their use. But prescription schedule 2 labeling would not be_necessary if we take away obesity as an indication for their use Finally, this Select Committee on Aging, looking at the relationship of drugs to the aged, looking at the way information is to be given out on drugs, must look very carefully at a new danger that is rapidly approaching, and that is the danger of allowing drug houses to advertise directly to the consumer for _prescription drugs as well as for the over-the-counter drugs: That may be considered to be another issue, but I beseech you to look at that issue very carefully as well. Portions of the drug industry; not all to be sure; are very rapacious and they cannot be allowed to expose the trusting consumer to its high-powered promotionol tactics unshielded. Lpause there and wait for questions. [The prepared statement of Dr. Prout follows:]

PREPARED STATEMENT OF THADDElls E. PRouT. AS_sOCIA_TE PaoFF.ssort oF MEDI- CINE; THE JOHNS HOPKINS UNINIFRsITY; AND CHIEF OF MEDICINE; GREATER BALTI- MORE MEDICAL CENTER Members of the Committee: I am Thaddeus E. Prout, M.D., Associate Professor of Medicine at The Johns _Hopkins University School of Medicine and Chief of Medi- cine at the Greater Baltimore Medical Center. I have been asked to reflect on the use of drugs in the treatment of obesity, - I am no stranger to this problem. My concern began over a decade and a half ago and has allowed me to be a part of a battle against false advertising for drugs related to obesity which has been successful in all of those confrontations that actually came to trial. The most recent of the cases concerning phenylpropanolamine (PPM was in association wiCa the Attorney General of Maryland concerning a public hearing held on January 25, 1981, against the Consumer Publishing Company, North Canton; Ohio; National Pharmacals; Canton, Ohio; Richelieu Pharroacals _Canton, Ohio; and the president of the Consumer Publishing Company. A copy of the final order against the defendants is appended. In addition, this will be my fourth appearance before a committee or subcommittee of Congress in association with misrepresentation of the therapeutic efficacy and safety of pharmaceutical products. I am chaiman of the committee on pharmaceutical agents for the American Society of Internal Medicine; a Fellow of the College of Clinical Pharmacology; and_president, founding member, and member of the Board of Directors of the Society for Clinical Trials. All of these organizations have an i_n- terest in these procedures; butdo need to stat : unequivocally that I speak today not as their representative but from my personal study and conviction: Further, I -am- a duly appointed member of the Planning and Evaluation Task F'orce of the National Council of Patient Information and Education under the leadership of a former and illustrious chairperson of this committee, the Honorable Paul G. Rogers. In the tradition of this committee, past and present, I am dedicated to the rational use of_drugs of proven safety and efficacy. The issues in most of the former battles have tended to _conce_ntrate on the question of the effectiveness of these agents; but I should like to begin, as I said_ before Senator Gaylord Nelson = almost ten years ago; "The final judgment as to the efficacy of a drug is based on the benefits derived from the drug in contrast to the risks inherent in the use of that drug. This is frequently spoken of as the risk-benefit ratio. If there are no great benefits to be derived from the use -of a pharmaceutical agent, there would seem to be little justification for the use of this agent since some risk inherent in the use of any foreign chemical in human subjects. The use of pharmaceutical agents with harmful side effects and little usefulness cannot, in fact, he justified." 100 There is nothing new about the attempt to use PPA for the treatmentof obesity. In 1948 the late R. A Williams, M.D., later Professor of Medicine,chairman of the Department of Medicine, Washington State University, and the foremostendocrino- logist in the United StateS, Stated,Of eight amphetamines tested, PPOAAPPM ranked seventh while Dextroamphetamine was first asregards their relative effectiveness in ability to suppress the appetite." For the next twenty years,_PPA was used principally as a nasaldecongestant since it was not effective for weight reduction. In the mid sixtiesresearch funded-by individuals interested in promoting the unlikely_possibility thatthis was an effective drug in the treatment obesity appeared, and a controversy overthe effectiveness of PPA as an anorectic agent immediatelyfollowed In 1976 an advisory panel of FDA reviewed the literature onthe safety and efficacy of PPA anc) concluded that PPA was safefor adults as a cold remedy in specifically recommended doses provided there were no contraindications.In 1978 a second advisory revie v panel was con ened by FDA for the purpose ofreviewing the evidence on PPA as an aid to weight reduction for over the counter useA tentative Statement for the advisory review panel issued_in December1978 concluded that such products are safe and effective for OTC use when the amountof Phenylpro- anolamine contained in the produtt is within the recommended per dosef25_to 50 mgs.) and daily dosage (not more than 100 mg )amounts." In reaching this condo- sion, tbe panel _depended on the previous findings of safety for coldremedies and on unpublished reports for evidence of efficacy. In the treatment of obesity. the prototype medication amongthe amphetamines and its congeners, of which PPA is a minor member, hasalways been Dextroamphe- tamine. In 1974 an extensive review was undertaken_of _dataavailable from legitimate pharmaceutical firms concerning the efficacyand safety _of _amphetamines as a treatment for obesity. Over one thousand reports werereviewed from_which two hundred studies were analyzed by the committee of which I waschairman. There was evidence of only trivial weight loss byindividuals taking these powerful drugs over those taking only placebo. Thecommittee was able to conclude that the differences in weight loss between the two groupsof patients was confined to a few pounda over a period of from eight to sixteen weeks. Moreover,this difference was already leSeened with time over even the short span of thisstudy. Subsequent review of these medications following failure of the committee'srecommendation to be enforced led to a recommendation that obesity bewithdrawn as an indication for the use of these drugs, and this has been accomplished. When the FDA Advisory Review Panel on MiscellaneouSInternal Drug Products gave its report on PPA in 1979, it relied heavily, asnoted previously, on the earlier report of the advisory committee of the FDA for evidenceof safety as it was applied to PPA as a cold remedy. Evidence of efficacy forthe treatment of obisity was-based on report§ Which are largelyunpublished. Although the FDA labeled this a "Tenta- tive Report", the FDA haS, by its silence; tacitly allowedthe tentative conclusions to become public policy. _as a result, both sales and profits morethan doubled for one company alone between the first ninemonths of 1979 and the same period in 1980. Sales and profits have continued upward since. Earlier it was_ noted that PPA stood seventh in a list ofamphetamines as to potency in relation to its ability to control appetiteWe have seen that the most potent of these agents yields only trivial reductionin body weight under controlled studies. Thus there is no scientific justification for thefinding that a prochict one seventh to one -tenth as potent as the major drugs inthis field could succeed in counter distinction to the parent c,,mpound. Turn;ng now to the queStion of safety, an additional note ofcaution must be raised. Encouraged by manufacturers through false advertising,the use of PPA can be dangerous. The medical literature- contains many reportsof serious adverse effects following the use of this medicine. There is evidencethat these drugs ha're been associated with acute lysis of muscle cells withsecondary renal failure (JAMA 248 :1216; 1982); severe elevation of blood pressurewith myotardial_ damage (Br. Heart J. 47:51; 1982), cardiac _arrhythmias (C/in.Toxicol. 7573, 1970; Can. Med Assoc. J. 119:729, 1978); chest pain in_ normalpatients (Med. J. Austral. 2:497, 1978; Lancet, 2:60, 1980); cerebral hemorrhage_ (M.ed. J. Austral.2:258, 1959); psychic reactions to even a Small dose of PPA such as mania_andhallucinosis (A. J. Psychiatry 138:392, 1981; JAMA 245:601, 1981); as well as street abase,seizures,and death from overdosage (JAMA 245:1346, 1981). Sinceunder-reporting of all adverse drug effects is well documented, there can he no question ofthe potential dangers inherent in the use of this medicine. From this review one can agree with Bennett that "anyamphetamine with actor- exic properties has the potential for causing untowardsCNS side effects regardless

:4; 101 Of the manufacturer's claims" (Psychosomatics 4:327, 1963). In brief, no drug has been shown to have even trivial effects on appetite which was at the same time sefe. The two effects are completely interlocked. As an over the counter drug, PPA may be obtained by anyone without regard to special risk factors. This is of special concern in regard to the aging patient. These drugs which do little to control weight are especially dangerous in this group.- Obesi- ty increases with ..,;e and is associated with hypertension, cerebral vascular disease, heart disease, andiabetes. In addition, in -their pursuit- of -youthful appearances, the aging population has become a susceptible group for the false advertisement related to the use of these drugs. These are the individuals at risk for central nervous system symptoms, cerebral vascular accidents, hypertensive crises, myocardial in farction; congestive heart failure, arrhythmias; and hyperglycemia. I began by pointing out that I have been involved with a "one-on-one" confrontation- with single manufacturers concerning the advertisement of single name drug productS, but I have come to realize that this does little to resolve this problem. Delays of court action, appeals, and eventually the changing of the company name or the company product all serve the producer at the risk of the consumer. Action of this committee in the creation of Legislation to_prevent these abuses will do much to change this picture. Not only can this prevent the direct abuse of the consumer by a rapacious drug industry but it might also become the prototype for further reforms concerning drug advertisement generally. Unfortunately serious consideration-is being given currently to allow the drug industry direct access to the consumer for all drugs through advertisement. Expansion of their legal right to do this would bi a grievous error on the part of Congress or of the FDA. The example which we are discussing this moaning in relation to PPA an_d,specific_ally as_it relates to_the_aging population is but a small portion of the problem that will develop if the right to direct advertisement is expanded. This committee should consider its role in preventing the abuse of the population most likely to be harmed by excessive advertisements. Ms: _OAKAR, Thank you very much; Doctor; Dr. Ramey? STATEMENT OF DR. JAMES RAMEY Dr. RAMEY. Ms. Oakar, thank you for inviting me to speak today. My name -is Dr; James Ramey; I'm a physician and I specialize in endocrinology and metabolism. I'm on the faculty of George Wash- ington Medical School and I'm a consultant to the National Insti- tutes of Health and to the Veterans' Administration Hospital. It's my view that the over-the-counter diet medicines containing PPA should be removed from the market because they are neither efficacious nor safe; As others before me have said, they are particularly of danger to elderly patients. In reviewing the studies purporting efficacy; I was wondering if any of the people who have done any of those studies would be willing to take a group of 65-year-old overweight people, not measure their blood pressure before they started the study; and give them phenylpropanolamine for 6 weeks to see if they lose weight and to see if anything bad happens to them. That study has not been done and I would predict that it would never be done because the drugs look to be unsafe enough that no responsible investigator would be willing to take the risk. Now, why io I think that they're not efficacious? The gold standard for the treatment of obesity is that the weight loss has to be sustained for at least 1 year and probably 2 years. Obesity is a chronic disease that lasts; generally for the lifetime _of the person once they become obese. It's like high blood pressure. No one would advocate that a drug be sold for the treatment of hypertension that lasted for 6 weeks and then you stopped taking the drug. Because 1O 102 hypertension is a chronic disease which needs to be treated life- long; as does obesity. So, in evaluating any scientific study that's presented to you about the treatment of obesity; you have to see whether the weight loss has been sustained for 1 year or 2 years. NoW these drugs, as you know, the studies last generally between 4 weeks and 8 weeks; There is no study of any of theSeoVer=the; counter Medicines that documents sustained weight loss for atleast 1 year, and therefore, none of these studies; no matter howwell done; are scientifically valid for the treatment of this chronic illness. Now, given that the studies don't meet the gold standard, Which in my testimony I have submitted in writing, that_gold standardis presented in all the textbooks of endocrinology and metabolism, and none of them advocate using any kind of medicineSfor the treatment of obesity because none of them have been shown to be effective. They don't even mention these kinds of medicines, I might add; Given that look at the short-term studies that the drug companies, by and large, have presented as evidence that these drugs are effective; in the short run, for a period of 2 to 3 months. What astonished me, and I've read, I believe, every study that's been published in this matter; -what_ astonished me, first of all, is thatI've never heard of any of the journals that theyhave been published in. Including the International Journal of Obesity, which Ihave now heard of. And the reason is when I was doing scientific research on drugs; what you did first when you did a study was yousubmitted it to the New England Journal of Medicine,_and if they rejected it,then you sent it to the Annals of Internal Medicine, and if theyrejected it you went down the list until you found somebody thatwould publish it because if you didn't publish it, you didn't getpromoted. Well, I never got down to the International Journal ofObesity. On the other hand; I'm now in private practice. If you look at the scientific validity of these studies, the reason that they haven't gotten into the New EnglandJournal of Medi- cine is that they are poorly done studies. Many of themactually haven't even been published. They've just been submitted tothe Food and Drug Administration; If you look at the waythey do their controls, if you look at the way they do their statistics, most of them you can't even ft-ure out whether the statistics aregood enough because they don t give you enough information inthe study. So, scientifically speaking; the studies that purport to showthat they caused some weight loss are bad studies and shouldn'tbe used for spending $200 million a year Now, given that; look at the advertisements on television.If yeti look at the advertisement§ on television you would thinkthat if you took those drugs for a littlewhile you d get to be as slender as I am. Well; the fact is that that's what the drug companieswould like you to think from their advertising. Ifyou actuallylook at the Studies which they used to purport to demonstrateweight loss, the maximum amount of weight loss, on the average, isabout one-half pound a week. 103 Now, I see probably, in my practice of a dozen years, I've probably seen 400 or 500 people who come to me as a_specialist in the treatment of obesity; Now, if] told one of those 250-pound people sitting across from my desk that under my expensive and sophisti- cated regimen at the end of 3 months that they would be 5 pounds lighter; they would stand up; walk out of my office, and refuse to pay my bill. The fact is if the public knew that they wouldn% lose very much weight; even in the short run; and that they would be back to the same weight in the long run; they wouldn't buythese medicines. In treating all these people with obesity, I must say that- I'm very bad at treating patients with obesity. In every good scientific study looked at; the success rate is no bigger than 5 percent. And I'm no better than anybody else. Hundreds of patients that I've seen; they usually come to me fairly late on; because' specialize in that disorder; Almost all of them have taken over-the-counter diet medicines and almost all of them lost a couple pounds, and none of them are any lighter by the time they get to see me as aspecialist. So; they don't meet even the most minimum standards, it seems to me, of effectiveness. And they are dangerous. And _I won't go into the details because people before me have done so. Rut it's my judgment that they are particularly dangerous in the elderly, because the elderly have a much higherincidence of heart disease and cerebrovascular disease; and to _subject them to the risk of taking a medicine which has no benefit, it seems to me, is entirely unjustified. And the elderly that I'm -most concerned about, given that I am a big city doctor, are the elderly poor, ofwhich there are a larg_e number in Washington, D.C., and if you go and look at the drugstore windows in the ghettos in this town; that's where you see the big advertisements for the over-the-counter diet medicines. You don't see them in Spring Valley. And the elderly poor are -the people most likely to take over-the- counter diet medicines, and they are quite likely to not be under medical supervision because they can't- afford it And; as a conse- quence; they are the least likely people to knowthat they have high blood pressure and heart disease and should avoid those medicines. So, and therefore; I think that these medicines should be taken off the market, since they are absolutely not efficacious, and therefore; as my predecessor said, since there is no benefit; no risk is acceptable; Thank you. [The prepared statement of Dr. Ramey follows:]

PREPARED STATEMENT OF JAMESN.RAMEY,M.D.,ASSOCIATE CLINICAL PROFESSOR; GEORGE WASHINGTON UNIVERSITY The- most significant nutritional disease in the United States is obesity. Obesity contributes to heart disease, diabetes; hypertension and lipid disorders. It is an extremely widespread disease and though it has been with us for as long as humanity existed,it has only Wen a problem in wealthy-countries where people can afford to ear more than their bodies burn. The cause of obeSity is stillunknown. We do not know why most_people overeat. There have been a host of possible explanations given; such as early childhood overfeeding, hereditary disorders, hOrmonal disorders and disorders of the part of the brain that controls eating. As yet, none of these

I 0Li 104 possibilities have been definitively proven to cause obesity. In part, because we do notknow the cause of obesity, we have been unable to develop a cure. What would be the definition of cure of obesity; a chronic disease which kills mil- !icing of- Americans a year and which causes countless others to suffer shame_be- cause of our youth-oriented, slender-oriented society? Any cure for obesity mustbe a long term cure. Obesity is a chronic disease. One is not obese for a day, or a week; or a month. One is obese generally for one's entire life. No expert in obesity considers any treatment for obesity as being effective, much less being a cure,unless it can cause substantial weight loss thut lasts at_least a year or two. Any modality which causes a small amount of weight loss that lasts a few weeks is, by the definition -of experts in obesity; an iluiffective treatment. If we compare obesity to hypertension, we have to realize that no one would consider a reasonable treatment for hypertension, which is a chronic life long disease, a treatment which lasted three to four weeks and which had never been proven to last- longer than a couple of months. The old standard for evaluation of therapies for obeSity looks at sustained weight loss of at least one year and preferably two years. Using that standard; no treatment for obesity has been effective in large populations of patiente for more than five to ten percent of patients: The most successful methods for the treatment of obesity are methods that motivate patients to eat less; in a balanced diet.. Programs such as Weight Watchers have in general been the most effective because they combine behavior modification with a reasonably de= creased caloric intake. The object is to shange people's eating habits so that over the long run they eat less: Since obesity has as a large part of its psychological component, almost any program -of weight loss which appeals to popular imagination works for a short period of time. Thus, fad diets recur in the American population. I first began practice ten years ago when the Atkins diet was popular. More recently, there was the liquid_protein diet and most recently is the Scaridale diet. All of these diets work and all of the nostrums- and medicines work in the short run because people are motivated for psychological reasons to lose weight in the short run. What iSneeded it a treatment which will work in the long run, ana that generally is behavior modification in which people learn to eat differently. The hope has been that helping people to start out losing weight with some drug or gimmick will enable them to change their dietary habits and loseweight over the long run. This hope has not been fulfilled. There is no way to lose weight other than a life long plan of eating less than one wants to These facts havemade treating obesity very frustrating for the physician, rot to mention the _patient. An honest physician- can tell his or her patient that the patient will have about a ten_percent chance of sustained weight loss at one -year if they go on his program of behavior modification and a balanced caloric reduction. If psychotherapy, group therapy, so- phisticated dieticians and a gimmick or two are thrown inthe- program -might be slightly more successful. I do not have -any gimmicks, and I in fact now do not encourage- people who are overweight to come to me for treatment asI am just as un- successful as anyone else: They see me in the desperate hope that there is something wrong with their hormones, but there seldom if ever is. I have seen hundreds of patients who are overweight. I have cured very few, and I have disappointed many. Hormones have always been normal. Most of the patients that I see in my practice have already filed at miltiple diets and multiple gimmicky programs. Many- have been to "fat doctors" and have b-een treated with shots and drugs which lasted onlya transient period time Almostall have tried over- the - counter appetite suppressants containing phe nylpropanolamine. None hat; achieved weight loss --of more than a few pounds that has been sustained for more than a few weeks. The major anorexiants are amphetamine-like agents and these drugs presumably exert their effects at the level of the hypothalamus.It is probable that they have a modest effect in promoting short-term weight lossin certain individuals. However; they are effective only for a period of a few weeksand problems of habituation; addiction and generalized drug abuse limit their useful- het:W. However, none of these agents treats the underkying_eating disorder sothey are, therefore, of little use in maintenance of weightreduction._ "The major problem in the treatment of obsesity is not weight reduction but maintenance of the richiced Weight." Provided -the therapist works hard andlong enough, most motivated patients can eventually loseweight.Unfortunately, only the rare - patient maintains the weight loss permanently. Obm:ity-is aneating disorder and the underlying mechanisms are not reversed by limiting f6od-intake. A quotation from the Textbook_of_Endocrinology by Williams (1982 ed) says"an appetite suppressant, usually amphetamine derivatives, are of limitedutility, since their effect is transient and rarely leads to more than a 10 percent weightreduc-

1 0.i 105 tion. Since the treatment of obesity is life-lang, such drugs have no demonstrable role in the long term management of obesity." Thus, it hu been demonstrated that any short term treatment of obesity which cannot be demonstrated to last for significant periods of time, usuallydefined as one to two years; is no treatment at ail. Then, for evaluating any treatment of obesity which is going to be approved if not granted FDA approval, the treatment -must be demonstrated to last far at least one year. No good study of obesity treatment demonstrates that any modality in a statistically significant way will lead to substained weight loss. Certainly no data suggests that amphetaminlike derivatives such phenylpropanolamine will lead to sustained weight loss. If they do not meet this standard of efficacy, then by my definition, they are ineffective drugs and should not_bc sold as if they were effective. It is given that with a little help starting out with weight reduction due to the drugs, people will learn new dietary habita This has not been proven and in -fact is exceedingly unlikely since it does not happen with any of the stronger amphetamine drugs. Accepting for the moment that these drugs do not meet the long term standards that the scientific community will- require for a weight reduction agent, let us see whether these drugs really meet the public's standard for a weight reducing agent. Contrary to what the package inserts and the advertisements would make people believe, the over-the-counter diet suppressant containing phenylpropanolamine appear to cause a very small amount of weight reduction. I have reviewed all the Studies that were submitted to the FDA when it had its original hearings in the 1970's. I reviewed several studies that have been published since then: The astound- ing thing, from the public's point of view, is that they in fact document that very small amounts of weight reduction are achieved with these medicines. Studies were conducted in which there was frequent visits to the clinics, where doctors or other health personnel were seen, so there was a great deal of phychological support for the weight reduction effort which always included dieting plus taking_the medicine. There was thus a large effect of the non-drug therapy that af;compartied the_drug. Therefore, in order to attribute any of the weight loss to the medicine you have to subtract what the control group, the group that did not get the medicine, lost. Over six weeks, which is the average duration of the studies, the average-person lost 2.7 lbs more that the control group. If I told a patient coming to my office that over a six week period they would lose 2.68 more than they would lose if I merely prescribed sugar pills, they wo_uld get up, walk out of my office and refuse to pay my bill. If the public realized that over a six week period they would be lucky to lose 3 to 4 lbs; that they would probably not lose any more than that even if they stayed on the medicine and that they would be the same weight a few months later, almost certainly these drugs would not sell- at ell. The small amount of weight reduction actually achieved by these drugs in the studies is not realized by the people who buy the drugs. It is astonishing to me that the FDA has accepted the-studies that have purported to show that these drugs work, even in the short run. The studies which I have- re- viewed are generally of poor technical quality and have either not been published and are held by the drug campanies, o_r have been published in obscure journals. Nowhere do you see any reports in the New England Journal of Medicine or the American Journal of Medicine or the Annals of Internal_Medicine or -any other reputable well-refereed presitigious medical journal. That is because these studiesnre poorly done. There is poor matching -of patients to controls. Unless you can show that the treated patients and the patients taking the sugar pills were the same in most respects, you cannot show that any difference , was due to the drug or to the differences in the patient populations. Frequentib the controls started off at different weights than the treated groups. The time periods used were very short; often three or four weeks, _a pitifully short time to document weight loss since every program initially shows some weight loss. In these studies, the data given wasquite inadequate to determine, front an objective point of view, whether the study was valid or not The data only mentioned side effects casually and did not scientifically analyze the side -effects: One study, in order to make its nunbers_statistically sigc nificant, excluded-the treated patients in the study who had gained weight rather than lost weight. The studies had an unacceptably high number of drop outs from the program. Onp of the larger studies had a drop out rate of 34 percent of the treated group the study could be treated. Therefore, it is not at all clear to me that there has been- any demonstrated efficacy of these drugs, even in the short run. If thestudies that have been done are poorly -done and are not convincing scientifically then -one cannot say that these drugs even cause short term weight reduction. As I said before, even given that this 106 is true. most of these studies show only a few punds of weight loss over six weeks. This is clearly not acceptable to patients, and _might be acceptable to doctors if the weight loss was sustained for a period of year; but this has never been demonstrated nor even alleged: It is my contention that drugs sold over the counter should be efficacious and Safe. The efficacy even in the- short run has not been clearly demonstrated. The safety issue will be disscussed by others. I should point out, hbwever, that a different standard of scientific validity should be_given to fears of ill effects of over-the- counter medicines. Rigorous standards of proof that a drug is effective treatment should be required. Only in extremely valuable and therapeutically effective drugs can one afford to ignore reported of serious side effects. Many drugs which have serious side effects demonstrate them only in a few patients. To say that only 5 percent of patients had significant hypertension from taking these medicines may mean that hypertension may well not be demonstrated in a study in which an average of the blood pressure is done, which happens in many of these studies. The raw data in many of th., studies is not available for scrutiny, but upon scrutinizing some of the data that has been made available; it is apparent that in some patients taking these drugs the blood pressure rises dramatically. Since these patients are not under medical supervision, whether or not the blood pressure goes up is not going to be known to the patient. The drugs are all amphetamine-liked_rugs and it is therefore likely that they cause some hypertension, and, as will be shown by other people testifying here, these medicines do cause hypertension in some people. They can also cause insomnia, irritability and a variety of other minor side effects. They can certainly aggravate hypertension in individuals who already have it. There have been many reports of serious side effects such as malignant hypertension, seizures, coma and serious psychiatric disorders precipitated by thesedrugs. While these are only case reports and are usually not clear reportS, as people have been taking other medicines, they have to be taken seriously since these drugs are so widely available and are used by people not under medical supervision. These medicines are particularly dangerous to older patients. Since these patients are more susceptible to the effects of hypertension in terms of rather modest rises in blood pressure precipitating heart attacks and stroke; it is particularly important that older patients be assured that these drugs do not harm them. I _do not think that the package inserts warning that you should not take these medicines if you have high blocid pressure are sufficient. People taking these medicines, especially older people, do not known that they have high blood pressure; they do not know that they have serious heart disease which may be aggravated by taking these stimulants. lt is important, therefore, that these drugs not be_promoted for older people. Furthermore, it is not demonstrated that older people benefit from minor decreases in weight; since frequently these people are dieting in order to treat hypertension or diabetes, and a few pounds of weight loss is not going to make a difference in those diseases. Particularly the-unsuspecting elderly poor are at risk. They do not have access to medical care to find out if they have underlying disease if they know they are overweight and try to do something about it by taking one of these over-the- counter medicines which are so widely promoted. It is my suspicion that these medicines are more likely to be used by people who cannot afford traditional medical care. They, therefore turn- to an unexpensive nos- trum which might help them. These are people much more likely to have hypert_e_m. sian, heart disease that has not been detected previously because they have not been able to afford medical care. These are the people that are most at riskthe elderly and the poorthat I believe are most likely to take themedicines. In summary, the over=the-counthr diet medications containing phenylpropanolamine have not been proven to be efficacious for the treatment of the chronic disease known as obesity. They produce very little weight loss even in the short run and have- the-possibility for serious side effects and should not be sold over-the-counter in the United States since they are neither efficacious or safe. Ms. OAKAR. Thank you very much, Dr. Ramey. Mr. Lantos? Mr. LANTOS. No questions, Madam Chairman. Ms. OAKAR. OK. Ms. Ferraro? Ms: FERRARO. I have to tell you; looking at the four doctors there, I just want to ask you, do you schedule this as a house call? My question is this We have, and I'm going to pick up a little bit on what my colleague started to address to the previous panel. Just

111 107 how much involvement is there with the elderly and these diet pills? You have indicated, Doctor, that thin is young and young is wonderful to the elderly; and we have had testimony from Dr. Mueller about high blood pressure, hypertension, is a problem with these diet pills, and if you put the two together you're going to have a- problem; if you have elderly taking them. It seems like it's a schedule for disaster. Are there a lot of people who want to get thin? I mean what's the size of the problem that we're talking about? Because I thought as you got older you eat less, as a matter of fact. Dr. PROUT. I take it you're addressing that to me? Ms. FERRARO. Yes. Dr. PROUT. As one gets older, you may eat less, but you save more of it, and you do get fatter. I used to argue with another pharmacologist who stood on the other side of this question when he said that we had no right to be concerned about _a young woman who only wanted to use PPA to get into a size 12 dress for her son's wedding. Well, we heard from a young woman this morning who did just that. My rejoinder, without having a name to give to her at that time, was, "Yes, we do, if it's dangerous, and there's no benefit to be gained from it." And I continue to _hold that position. Youth is slim and youth is beautiful to the elderly. They try to attain it. We also see this with exercise programs. Our accident rooms are sometimes filled by older people who think that if they exercise just a little more strenuously they will get there a little faster. So, the urge to do slightly more than is necessary is a common problem. They will take these agents; and in excess: I don't have statistics on actual use but I believe our cochairman had some evidence that they were being used. I don't know how many. Obesity, hypertension, arrhythmias, hyperglycemia, cerebrovascular diseases are all interlocked as part of the problem of aging, and it is about those people that we are very much concerned today. Ms. FERRARO. Let me ask what may seem a little bit far out as a question with reference to the elderly: Dr. PROUT. Not at all. Ms. FERRARO. Have you ever seen an elderly person who has taken diet pills as an appetite suppressant because they could not afford to buy food? Dr. PROUT. I would always like to have that kind of confrontation because the price of the proper_food is always less than they are presently eating. At the price of food in the supermarket today, I can save them a lot more money by having them restrict their eating to a proper diet than they can ever get by eating what they are eating and taking a magic pill. I can save them a lot of money. The answer to your question is I have seen people say that they can't afford a diet; but not after they got the second half of my sermon. Ms. FERRARO. Obviously it's not safe and obviously if you-- Dr. PROUT. It isn't correct to believe that you must take the pills because it's cheaper, in order to lose weight. 11 108 MS. FERRARO. No. What I meant, Doctor, is are there people, not to lose weight and put that in a comparison with thethousand calorieswhat I'm saying to you is are there people who come in who say, "I've taken diet pills because I just can't afford to buy foOd"? It does suppress your appetite; at least in the anecdotal. I remember that when I took them that 13, 14 years ago, I didn't eat anything at all. I mean, I was a total wreck but I didn't eat anything. Dr. PROUT. But we're- talking about a lifetime of obesity. MS. FERRARO. No. No, I'm not talking about that. Forget the obese people. Dr. PROUT. You're talking about any kind of weight loss? Ms. FERRARO Any individual. Dr. PROUT. OK. Then we're talking about a third to a half-a- pound week over-- Ms. FERRARO. That's not what I'm talking about either. I'm talking about the individual coming in, an individual who is elderly; who comes in and has had a reaction to a diet pill, and is taking those diet pills and when you look at them you say, "What in God's name are you taking diet pillsfor?" and they say to you, "I'm taking it because I just can't afford to buy food; I've run out of my social security check. I've run out of whatever it is." I mean,do you ever have that kind of statement made toyoti? Dr. PROUT. Oh, I'm sorry to have misunderstoo you; MS. FERRARO. I'm not talking about someone that wants to lose weight: Dr. PROUT. Do patients use pills to take away hunger becauseof an inability to buy food at all? Ms: FERRARO. That's what I mean. Dr. PROUT. No, I've never had that experience and I doubt if i.-4ny of the other physicians have, ever; MS; FERRARO. Has anybody on the panel ever had that experience with the elderly? [No response.] MS. FERRARO; Have you, Dr. Mueller, had any experience atall with the elderly, because yours seem to be mostly young kids? Dr. MUELLER. I'm a neurologist and so I see strokes all thetime MS. FERRARO; Yes. Dr. MUELLER. And, of course, most strokes occur in theelderly; So, I see strokes all the time In the elderly strokes that Ihave seen, none have taken diet pillsprior to their stroke. MS. FERRARO. None. It's just an interesting thing. Thank you very much, Madam Chairman. MS. OAKAR. Thank you. Did you want to respond, Doctor? Ms. FERRARO. Oh, I'm sorry. Dr. RAMEY. I see a fair number of patients; in response to an ear= her question; I see a fair number of patients in my practicewho are over 65, who are overweight.My oldest patient in my practice is 107 years old and he weighs 225 pounds; MS. FERRARO; But again, the people I'm speakingabout who might, where I was going was the necessity to take thosepills in order to not pay for food; would not be coming in to see you, Doctor; as a private patient, at your fee schedule which youhave 109 just alluded to in your prior testimony. Thankyou very much; DOctor. Dr. SCHWARTZ. I think there is something that;before we leave, you shouldn't lose sight_of, because we have been talking specifical- ly_about the diet aids. Perhaps the best testimony I'veheard this morning came from the chairman when he discussed thepolyphar- macythe multiple drug therapy. Not only dowe have difficulties predicting what toxicity of an individual drug is inan elderly adult, but if we combine that with the 7 to 13 other drugsthat they are taking, we have an impossibla toxicologic situation. Dr. Mueller used the word "idiosyncracy," I think:An idiosyncratic response is an unexpectedresponse. But I tell you that these are not idiosyncratic responses; We expect_some toxicresponses in the elderly adult, based on the number of drugs theyare taking; This is espciall3 true for drugs which have onlytoxic side effects and very little other benefit And we're not talkingabout an unusual situation. It's entirely predictable. MS. DAKAR. I do have some questions for eachof youDr. Schwartz, you have really gone into the molecularstructure of PPA. Is it accurate to describe itas a stimulant or isn't it? There was a court case and I believe; Dr; Prout; you were the expert witness or one of the witnesses about that case. Is it a stimulantor isn't it? Dr. PROUT. I agree that its centralnervous system effect, and its stimulating effect are closely associated with amphetamine;It is very similar in structure and action to amphetamine. The closet similarity that PPA has to amphetamine is its effecton the blood pressure; Ms. DAKAR. Dr. Mueller; Did you have something? Dr.D MUELLER. Nevertheless, the two may be correlated. What causes the central nervous system stimulation also probably leads, in part, to the elevation of bloodpressure; In other words, the elevation in blood pressure is not totallya peripheral effect; but also a central effect; MS. OAKAR. I see. NOW; Dr. Prout, you have been talking about PPA foryears. Back in 1972, before Senator Gaylord Nelson's committeeand his hearing you submitted a lot of testimony warningus about this problem; particularly as it relates to the drug industry. Youwere asked to be one of the witnesses in California about misleading advertising when the Attorney General successfullywon this case against one of the drug companies that is in the market of producing over-the-counter diet drugs. Can you tellus a little bit about that case and what you found, in terms of advertising? Dr. PROUT. In terms of advertising or any other part of thatcase, I'm afraid I can't. It is one of the unfortunate facts that whenyou try to fight this problem on a one-on-one basis yourun out of time, energy, and money, and I was not able to really help out in the California case because I couldn't afford to take the time togo out there. I was not part of that case; MS. DAKAR. I see. Dr: PROUT: I was part of the case in Maryland,my home State, where I could just go downtown to do it There too the stimulant question was raised. It is my reeling that these drugsare stimu-

27-436 0 - 84 - 110 lants in the real sense of theword and that to ask thatthe word "stimulant" be taken out of theadvertisement would would be contrary to the pharmacologyand would falsify it even more In our Maryland cam forexample; we were concernedthat the public was not being toldthat there was a stimulatingeffect. The manufacturer leaned heavily onthe fact that there was"no cats; feine" and stated thereforethat the drug contained"no stimulant." But the amphetaminefamily-- Ms. OAKAR.. No* we haveextra strength diet pillswith caffeine. Dr. PROUT. That's right. Mg. OAKAR. They'_re on themarket now Dr, PROUT. But I was notin on the California casebecause I couldn't afford the time andeffort. Ms. OAKAR. I see. But you have been reallypursuing this question for along,long time. It must be veryfrtstrating to you to see it stilllarger than ever. Dr. Pitotr. My_ colleague on myright, Dr Ramey referred -to some work that actually cameout Of Dr. Williams'Textbook of En= docrinology, either. in 1980, or oneof the earlier editions. Asfar back as 1948 Dr. Williams wasalready doing work on these agents. I happened to be a houseofficer at the Boston City Hospitalat the time and my entrance intoendocrinology was in no small partdue to the fact that Dr.Williams was there. He found at that timethat PPA was less thanone-tenth AS strong as the grandfatherof the whole fathilydektroamphetamine; and that fact is one thatI keep coming back toWhen_we looked at could provide between 1972and 1974, the best studies that industry drugs were effi- and couldn't find _evidencethat the most powerful obesity, it is scientificallyimpossible for cacious in the treatment of pathways, that is me to believe that adrug's arting along the same one-tenth aS Strong and inaddition is used in less thanone-tenth the amount could be eipectedto get any kind ofefficaaibus results. Hence, I am very hard on theefficacy of thiS drug_ inaddition to its lack of safety. Yes;I have followed the trackof this drug for a long time and I'm yet to see anyevidence that it haS anybenefits whatsoever. Ramey, you made perhaps thestrongest charges S. OAKAR. Dr; drugs; And you, reallyattacked some against the over-the-counterbeen submitted to FDA infavor of these of the studies that have has Ms. Young I wanted youto over-the-counter drugs. And so of know that we do have anotherpanel that is responsible for some those studies. be talk- If you're interested in them,they; I am sure, are going to ing about their studies. If youwant to Stick aroundthat would be fine. I think we'd be interestedin hearing some of the specificQues- tions: But you mentioned youhad not heard of theInternational when doctors submit yourstudies, and Journal of Obesity. Tell me, usually have a Dr. Mueller; when yousubmit your studies, do you get it published? peer review before you portrayal of_the various journals_is Dr. SCHWARTZ. Dr. Ramey'sGeorgetown's Rank and TenureCom- absolutely accurate._ I'm on publish or mittee for the medical schooland when we get into the perish decisions we look atthe quality or she journal,in which the 115 111 faculty member has been publishing,and that quality is determined by the editorial policy andby the nature of the editorial board. If the journal hasroom for 25 manuscripts a year and it gets 24 to be reviewed, you cansee that it's not going to -be very §electiVe. So; Dr. Ramey is absolutely right.There are some journals at the bottom that are just trying -to getwhatever manuscripts-theycan get. I don't wish to portray the InternationalJournal_ of Obesi*y in that way because 1 know nothingabout it or its policy, and that would be unfair. Ms. OAKAR._ Someorimentioned that some of the studiesthat have been submitted to FDAon behalf of the diet pill industry have never been published; they'rejust the individual statements of the doctors? Dr. RAMEY. They doa scientific study and they Publish it in manuscript form and, submit itto the FDA. One presumes that they have submitted them toone journal or another, but the fad is that several of them have not, in fact,been published; M§. OAKAR. How about advertising?I was talking earlier about pressures being put on some of us andmy staff I was interested in a channel 5 story that I understood ran in New Yorkby Betty Fur= ness, who is kind of identified with theconsumer movement: She did a Series, and yet most of itwas broadcast out of the New York station. And then before her serieswas over,_ in the New York Times; they printed an ad fromone of the drug companies attack- ing Betty Furness; "Instant scienceby Betty Furness is no public service.' [The ad referred to follows:] 112

" . .'

Now we -have- another evening news Wesuggestedshe interview clociors drug stare from WNBC-TV. andiesearChscientists_who have The largetthis time is phenylpro- been studyingPPA extensively at prelotarnine or PP& INSTANT sattemic institutions, including the University CA California, New York You've probably never heard of PPA; 'Univeray.Mtns Hopkins University but it's on site over the counter in and elsewhere every drugttrire in nasal decongestants and appetite Suppressants. Right nowt FDA is-reviewing a 1979 report by its own Advisory _ His estimated that 40 million people Farrel on river-thecounter weight - annually take PPA tor a shiny -nse. control drug products, Which wrote: And 10 million take it in snuffer "Jhe Panel conJudes that phenyl- doses to reduce their appetitesa ptooanota_minehrirochloride is provertway_to_ballebuluing_waisk cserallyrecognizecras sate_andel- lines and health-destroying obesity; fectivewhen used for OTCiveight Nocornes13eny Furness with a 60- Owl in tht dome noted below." second sensation; Welk Belly, this txurfli.. Jnds like Some street people a_no TV personal- another headline health stare. In rad, Him may think PPA gives you a high; thoughtful scientific journalism but stierilisis know it's -more likely to would have sped a tot of viewers lower your appetite and dry up your something more to worry about. postnasal drip. We hope you'll tell your viewers a What abotil those doclors on WNBC- 'rew 01 the duller sidelights on PPA MESS some Wednesday_or Thursday night, TV's most recent pharmaceutical shocker? such asit works So tar; clinical stadia glair it does help people low Welk doctors_ the normal way to re- weight, and its slfrity record is better port adverse drudreactions is to the than aspirin's. FDA_and to your colleagues in their scientific journals. Suchpublication Where does this leave you if you are allows scientists rather than news- concerned aboulyour weighr? Well casters to sort out the evidence. But vievaysirra tree society must decide : some doctors have round it's easier for themselves; to gel on the tube with sensational II you are_cOncernesk write us anti charges we'll send you aresearch report on Maybe such medical advocates want PPA recently published in theinteh every drug lo beaprewription drug. nationalAntral-a Obes# (1982) 6, Who will pay doctors' bills then? national. Mediate? WNBC-TV_didn't have to scour the sidewalks forte facts about PPA. We provided Betty Furness with a bundle orpublished and unpublished Thompson Medical Company; lee; scientific literature 919 Third Avenue New Ye*. N.Y. 10022

117 113 Ms. OAK.1R. They went into all of thereasons why, which is obviously their prerogative. The curious thing tome was they only printed it for the Washington edition, not the New York edition where they could reach the people that heard the show. Iwant to ask why that was done. Also I want to ask the FDA people if they felt the ad was addressed to FDA. But FDA isn't here today. They can't come, they say; they're too busy. And here we're talking about some pills, in general the over-the= counter pills, that affect millions of Americans. I am specifically talking about diet pills that are a $200 million induStry, $10 Mil- lion of which are consumed by Americans. We've hadsome Wit: neSSeS who have suffered real serious physical problems because they took that stuff. And they don't have time to come today. And you mentioned, Dr. Schwartz, I believe, that you had had difficultY relating to them.-- Dr. SOHWARTZ. Yes. I want to make it quite clear that I havea great deal of respect for the FDA's current administration, because I know -both the Commissioner and _people who work with him closely. That, notwithstanding; there w_ as; starting from about 1980, through about 1982 when I was especially active in this with the Postal Service, that I had a very difficult time in getting any interest on the part of the Food and Drug Administration in this problem. We were primarily3 concerned with look alikes, but also with the diet aids that were advertised through the mail. It was only through the rather persistent and perhaps veiled threats ofa lawyer in the Consumer Protection Division of the Postal Service that we were, finally able to get information suchas autopsy reports that had been gathered by FDA investigators. This informa= tion was needed in order to deal with the look alike problem and to pursue some of the successful prosecution that the Postal Service had on the look alike problem. Ms; OAKAR. Thank you And thank all of you very,very much. Your entire testimonies will be submitted -for -the record andwe will continue now with our final panel of individuals. Ms. OAKAR. We have invited various members of the _industry. However, only one company responded, Thompson Medical Co., and they recommended that these members be part of our last panel; We're happy to have them. So, we do have a panel. __Dr: Silverman is a pharmacologist of Massachusetts College of Pharmacy. Would you, Doctor; come up and perhaps identify others who have also come with you? We would be happy to have all of the individuals. 114

PANEL 4INDUSTRY OFFICIALS,THOMPSON MEDICAL CO.,_INC., CONSISTING OF DR. HAROLD I.SILVERMAN, PROFESSOR OF PHARMACY, MASSACHUSETTS COLLEGEOF PHARMACY AND ALLIED HEALTH SERVICES; DR.NIATTHEW H.. BRADLEY, CAR DIOLOGIST. MIAMI HEARTINSTITUTE, MIAMI, FLA.; DR. CHARLES WINICK, PROFESSOROF SOCIOLOGY, CITY UNIVER- SITY OF NEW YORK; DR. RUDOLFE. NOBEL, DIRECTOR, CATHE- DRAL HILL OBESITY CLINIC, SANFRANCISCO, CALIF.; DR. AN- THONY CONTE, BARIATRICIAN,BEAVER PA; DR. MARIANNE SEBOK, PHYSICIAN, AFFILIATEDWITH J. F. KENNEDY MEMO- RIAL HOSPITAL FRANKFORDHOSPITAL AND ALBERT EIN- STEIN MEMORIAL CENTERPHILADELPHIA, PA.; DR. FRANK FUNDERBURK, THE _BEHAVIORALPHARMACEUTICAL RE- SEARCH UNIT OF THE JOHNSHOPKINS UNIVERSITY SCHOOL OF MEDICINE; EDGAR E.COONS, PH. D., PROFESSOR OFPSY- CHOLOGY, NEW YORK UNIVERSITY;JAMES SCHREIBER, JR., JAMES SCHREIBER; SR., ANDBARBARA RITZ STATEMENT OF DR. HAROLD I.SILVERMAN Dr. SztvEiiiviAisr. MS. ()awnWe have a rather fine panel. Ms. OAXAR. Would you all comeforward, please? Dr. SILVERMAN. Yes. Whydon't I just bring our panelists all up to the front of the room? Ms. DAKAR. That's fine; Dr. SILVERMAN. I'll present mytestimony and my intrdchictionof the panel and then each one o,these gentlemen and womenwill present their testimony. Ms. DAKAR. That's fine. Could wetry to get a feW morechairs around the table. We're having a moredifficult time accommodat- ing all_of you. Dr. Silverman, Would_youidentify for the record theindividuals who are part of your panel, as well asyourself, please? Dr; SILVERMAN. I'm sorry, Ms.Oakar; I did not hear you. A gen- tleinan was talking to Ms. DAKAR. I'm_ sorry. Would youidentify the members of your panel? We would be very pleasedto hear from each and every one of them. Dr. SILVERMAN. I have a preparedstatement for the cbmmittee. Let me first identify myselfand_then each of my associates. My name is Dr. Harold I.SilVerman. This is Dr; Coons,Dr. Conte; Dr. Bradley, Dr.Winick, Dr. _Noble; and Mr.FUnderburk. I believe that directly in back of usis Dr. Sebok. Ms. °AKAR; Thank you. Dr. SILVERMAN. M name is Dr.Harold I. Silverman. I hold a from the Philadelphia Collegeof Pharmacy doctor -of science degree of pharmacy at theMassachusetts and Science. I am a prOfessor the ex- College of Pharmacy and_Allied Health Sciences, and I am ecutive director of its PfeifferPharmaceutical Sciences Laborato- ries. My curriculum vitae hasbeen provided to the committee. I ani acting today as theleadoff witness for a groupof-physicians have given testimony to theFDA's advi- and scientists. Many of Us [PPM was gen- sory panel whichfound that phenYlpropanolamine erally safe and effectiVe as anappetite suppressant; Other§Of US 115 have done new research inresponse to the Food and Drug Admin- istration's request for researchon particular aspects of PPA. I would like to talk to you today about phenylpropanolamine,a drug I have studied and worked with forover 25 years. When I first became interested in PPA it had alreadybeen in use for approximately 20 years. In fact, the first medicalreport of its effectiveness as an appetite suppressantwas published in 1939; Since that time a considerable amount of research hasbeen carried out on phenylpropanolamine and contrary to some assertions that I have heard, we do know quitea bit about this drug, much of which is published; First of all, what is PPA? We know that it belongsto the cheiniz cal family of phenethylamines, and this includesmany important drugs. It shares similar chemical characteristics withephedrine, amphetamine, and phenylephrine; with majorexceptions. While amphetamine is a powerful stimulant,even at normal therapeutic doses, phenylpropanolamine does not exbibitany stimulant effedts at all, at recommended dosage levels; In other words, for all practicalpurposes; PPA is simply not a stimulant: The stimulant action of amphetaminecarries with it a very high potential for abuse; PPA; on the other hand, hasno abuse potential at all. This has been dramatically demonstrated,in animal studies which compare the reinforcement propertiesof PPA to those of amphetamine and other drugs of abuse. More importantly, studies of drug abuse patterns -inhumans have shown that phenylpropanolamine playsno significant role. Dr. Winick, an authority on drug abuse, will discussthis subject in greater detail. Now; let's turn to the area and question of efficacy. DoesPPA help you to lose weight? Most emphatically,yes, it does. In addition to the earlier literature, documenting the efficacy of PPA;over a dozen well-controlled clinical studies havenow been submitted to the Food and Drug Administration. This chart, which may not yet be uncovered; butwhich isover to the committee's left, and which I helped prepare; summarizes some of these studies; As you cm see, the average weight lossre- ported for patients who received and took PPA;was about 1.2 pounds per week, more than twice Lh weight loss thanthose that took a pla.lebc This means that ifyou take PPA over the recommended 1 :f -week period; you can certainly expect to loseon the average al:nost 15 pounds. A survey of almost 3,000 consumers who used PPA reportedeven higher weight losses. Of course; you have to reduceyour intake of calories in order to lose weight, something most overweight people have a great deal of difficulty in doing. PPA; with itsproven appetite suppressant qualities, can and does playa major role in helping overweight people change their eating habits, and this, thereby; leads to an increased and significant_ weight loss. Finally, I'd like to address the all-important issue of safety; -To date approximately 50 safety studies on PPA involving nearly 4;000 patients, have been submitted to -the Food and Drug Administra- tion. The results: No significant adverse effects have been reported in any of these studies; 116 There have been a number of isolated case reports;published in the medical literature In recent years; andthese have attributed adverse effects such as sharp increases in bloodpressure, heart rate, seizures; convulsions, Psychoticepisodes, and other serious problems to the use of PPA. When these reports areexamined in detail, however, they invariably deal withfrank overdoses, acc:den= tial or intentional; or combinations with otherdrugs. Or situations where the actual dosage used could not bidetermined nor could it be confirmed. TheSe isolated reports need to be viewed inlight of the hundreds of millions of doses of PPA that are safelyconsumed each year in this country alone AS either appetite suppressants oras nasal decongestants. The only report of adverse effects that claimedto be from a controlled study was carried out on medicalstudents in Australia; This study reported Fignificant elevation ofblood pressure following the ingestion of an Australian PPAdiet aid and a somewhat lower increase when a PPA nasal decongestantproduct was used These unusual tesultS can be partiallyexplained by the fats that some of the doSageS used inthat study were considerably, consider= ably, higher than those recommendedfor use in this country. In addition to which, it haS never yetbeen clarified whether or not it -was truly phenylpropanolaminethat was used in that coun- tr3% My own research neverconfirmed that phenylpropanolamine had been used More importantly, however, these Australianresults had never been obtained before, nor have they beenreproduced in any other study either in Australia or in thiscountry. With this in mind I would only conclude that this study hadserious flaws and should be discounted. In concluSibn, my own research onphenylpropanolamine and my extensive review and study of the medicalliterature has convinced me that this is a safe andefficacious product when used as directed. I am in complete agreement with theunanimous findings of the FDA advisory panel which stated:"After a thorough investigation that phenylpropanolamine is generallyrecognized as safe and efficacious when used for OTC weight control." Thank you. Now I'd like to introduce my colleagues atthe table so that they can now provide a1-minute statement, if I might have yourkind- ness and indulgence. Mg. OAKAR. Fine. I'd be very happy toheat from each and every one of them. Dr. Siz.VERmAN. Dr. Bradley is fromthe Miami Heart InStittite and may we first hear from Di.Bradley, please. STATEMENT OF DR. MATTHEW H. BRADLEY Dr BRADLEY. Thank you I'm MatthewBradley; M.D. I'm en= gaged in the private practice of internalmedicine and cardiology in the Miami area I'm vice presidentand trustee of the Miami Heart Institute; I'm a member of its researchcommittee; and I serve on its publications and review committee.

12.i 117 As a reviewer of research;a conductor of original research, and as a cardiologist,_ I have been involved in bloodpressure studies for some years: Currently, I am evaluating the safety of phenylpropanolamine or PPA; an ingredient in theover-the-counter aids and cough cold products used daily by millions. In my study over 6 weeks, PPAwas used in the treatment of obese patients with controlled, stable;hypertension. This study found no clinically significant differencesin the patients' blood pressures or pulse- rates at either the 75 milligram time-released dose or the thrice daily, 25 milligram dose. We also found that PPA greatly reducedor eliminated hunger pangs and thus was effective in aiding the patient to loseweight: No side effects were reported. I _am now conducting a larger studyon controlled hypertensives, and while the study is not complete,-I- can tell you on this side effect issue that none of the 28 patientswho have completed thiS study have reported any adverse reactions. From my own research;_then, and theresearch I have reviewed; I can only conclude that PPA diet aidsare both medically safe and effective: Thank you. [The prepared statement of Dr. Bradley follows:]

PREPARED STATEMENT OF MATTHEW H. BRADLEY, M.D.,CARDIOLOGIST, MIAMI HEART INSTITUTE, MIAMI, FLA. Good morning, my name is Dr, Matthew 11._Bradley.I hold a Bachelor of Science degree from Kent State University andan M.D. degree from Ohio &Atte University. I am certified by the American Board of InternalMedicine and am a Fellow in the American College of Physicians, the American Collegeof Cardiology and the Ameri- can College of Chest Physicians. I am -a member of the Board ofDirectors of the Miami Heart Institute and of the Research Committeeof the Miami Heart InStitute. In addition to being a Clinical Instructor in Medicineat the University of Miami School of Medicine, I am engaged in the privatepractice of Internal Medicine and Cardiology in the Miami area. Lam also an active researcher in coronary heartdiseases and have published a number of papers- in such journalsas The Journal of American Medicine and The Jourtial_of Clinical Investigation. In 1979, the FDA's Advisory Review Panel on -OTCMiscellaneous Internal Drug Products submitted its findings that phenylpropanolamine(PPA) was "generally safe and effective for weight control." The Advisory Fanelhad reached this conclusion after four years of reviewing the literature and thedata submissions and after listening to additional testimony. It was hardlya rush to judgment. However, while the FDA was considering its Advisory. ReviewPanel's finding, two studies were reported in Australia which suggested that PPAmight increase patients' blood pressure. Accordingly the FDA asked study on this question. researchers to conduct further I -have been involved in this bloodpressure issue as both a reviewer of research and as a conductor of original research. For thatreason, I want to describe to you a pilot study that I have recency concluded,a pilot study that led to a study presently under way. The purpose of the pilot study was to evaluate the safety of PPAin the_ treatment of obese patients with controlled, stable hypertensivediseases. We selected 12 patients, varying in age from 25 to 67, all at least 10percent overweight and all of whom were being treated for hypertension. Why-bother to study PPA's safety for hypertensive patients;when it is not recommended that they use PPA except under _a doctor's care?Because scientists, ddctoni and the FDA want to be exceptionally careful, and testing very informative. extreme cases can be The study_found_no clinically significant differencesin the patient's blood pressures or pulse rates from when these patients began the study and whenthey_fin- ished it. Nor did we find any clinically significant differencesin blood pressure or pulse rate at the one-half hour, one hour, 2 hour andfour hour periods following 118 doses. Nor did the first medication dosage for the25 mg, the 75 nig o flee wefihd any significantblood pressure or pulse rate u reneee within treatment weeks, either. . Was the PPA effective? YeS, ih bothappetitesuppre01.T1 end Weight loss. NitietY three percent of the patients reported that theyexPeT511Oed hone or only dig?! hunger feelings after receiving either the 25 mg orthe ttlg dose of PPA But 4 4 percent of the patients reported moderate ormarked Hunker PINS aftef receiving (veins When patients took PPA doges, they experienced a --1--cumulative weight los0 in excess of one pound per Week. Whenthey took theirattfikbe theyexperienced mean cumulative weightLoss_ofslightly more than one-I:et bound per week. These results were obtained in n cresse'm stadY -that extendedfor too, nihIgof PPAthreetimes9 six weeks. Miring the first two weeks; each patient twice a day. In the day. In the second two-weekperiod;each patient took last two weeks, each patient took atime-released 75 dose of PPA once a daY. The middle two week period not onlyacted as a contrjoltodth;ek)re4btyalrseottdoeraillow arlY. PPA Which might remain in the system to bewash the results of the finaltwoweeks of the test. Each patient was checked weekly for bodyweight, teMkratttrei blood_pnrgesysualrice: pulse, both degree and -cili:Aida of appetitesuppregelorl!lki side effects. Every two - weeks, each patient received a full Physicalexaminetfes!u' rOludleg an electrocardkr riipli while lying down; as well as blood pressureand k feedings one-half hour, s' thaVY. une hour-, 2 hours and 4hours after the- initial dose frore Ten of the initial 12 patients completed thestudy.,,,were discontinued becausehis hypertension beingcontrolledby ,a the study after two weeks, one roeoP_V of previous time commit" drugthat violated the test_Protriccil and the second thehts. Neither of the two reportedhaving any adverse reported; or was observed tohave, aiiy iteeta._ No patier in tj3rogresk Itis far tooearIY I have moved into a large-scale study which is now the28patients who have to report on that study.However, I ran tell you that-1 completed the parts of the Andy titii:zing25 mg of Prtilree times a day and the placebo; none have reportedanyside effect5, either. ,al, espeC_1 forthe eoeoerne of this_ What my pilot study does demonstrate, thoughmedically 44 and effective; evenfor subcomthittee,is that PPA diet aids are both those with stable, controlled hypertension. Thank you. M§. DAKAR. Thank you verymuch, Doctor' P,.,% Charles Winick,ri SILVERMAN; Now; before I introduce and if .1, internationally authority in the area rl drug abuse, can haveyOtitindulgence; Dr: Winick, VI/P have with us three they don't hail& arlYPrekeed statement; are consumers who; while and available to the committee for_questions;§h-P'Id there be and, who have used_ appetitesuppressants_contairlitig Phenylptopanola- mine, finding them to beboth safe and efficftotis; Mr. Mrs; _Barbara Ritz is bete. Mr.JamesSchreiber; Sr.; and James Schreibee, Jr. Now, let us hear from Dr; WiniCk. Ms. OAKAR; Would they stand up, atleast' for us? So we cantake a look at them? Dr. SILVERMAN. Thank you: Ms. DAKAR. Thank you verymuch. Wed be happy to havetheir testimony '01' the record, ifYou would like; Dr. Silverman. That Would be fine. Dr.SILVERMAN.Thank you very much; front And after the panel has concludedif _they c°41d come to the and-present a Sheet statement;it wouldbe very gracious of you. MS. DAKAR. Fine. ___ Dr. SILVERMAN; Dr. Wiiiickfrom theCity University of New York; Dr. Wiriiek? 123 119 STATEMENT OF DR. CHARLES WINICK Dr. Wmcx. Madam Chairman andladies and gentlemen: Iap- preciate the opportunity of appearing herebefore you today. My name is Charles Winick. I hold a Ph. D. in psychologyand am a professor of sociology at the City Universityof New York Graduate Center, where I regularly teachcourses in drug abuse. I am editor of the Yearbook of Substance Use andAbuse, and also a psychologist in private practice; I hope to be Submittinga written statement for the record, and I would like to summarize that foryou now. For more than 25 years I have- beenactively researching trends in drug abuse and I have supervisedinterviews with 160,000 drug abusers about the substances they take, thecontext in which they take them, and the gratifications which thedrugs provide._I regw. lady track emerging substances of abuseand monitor the degree of their popularity. In this connection, I have been followingthe use of PPA in the United States for some years. Letme make some summary state- tnents about my conclusions on FPAas a substance of abuse and/ or addiction. PPA does riot meet the criteria for beinga- drug of abuse or addiction; It does not lead eitherto physiological or psychological dependence. It does not providea rush or a high. The body does not develop a toleranceto it.It does not damage the organs of the body. And it has no significant dysfunctional effects. Indeed, PPA is not a drug of choiceor even a secondary drug of choice among drug abusers. In fact, in theFederal Government's most recent report fromits Drug Abuse Warning Network [DAWN], PPA accounted for less than one-fifthof 1 percent of all the substances mentioned, and ranked102d among those substances that were mentioned. In just-completed national studies of trends indrug abuse among high school, students andamong the general population, sponsored by the National Institute of Drug Abuse,PPA was not cited as a drug of abuse. In conclusion, all available_clinical and epidemiologicaldata consistently demonttrate that PPA has not beenand is not a drug of abuse. [The prepared statement of Dr; Winick follows:]

PREPARED STATEMENT OF CHARLES WINICK, Pm, D., PROFESSOROF SOCIOLOGY AT THE CITY UNIVERSITY OF NEW YORK Good morning. My name is Charles Winick. Lholda Ph. D. in social psychology from Na i, York University and ama psycholopjst in private practice. In addition, since 1966, I have been professor of sociology at the CityUniversity of New York Graduate Center_where I regularly teachcourses on trends in drug abuse. I am also an active researcher in the drug abuse field. Among the sponsors ofmy studies have been the United States Senate Subcommitteeon Juvenile Dolinquency, the National Institute of Mental Health, the National Institute of Drug Abuse,the White House Special Action Office for Drug AbuSe Prevention, the WorldHealth Organization, and the American Association Against Addiction. At the American- Ski& Health Association, I started_whatis now the National ClearinghciuSe on Drug Abuse Information. My articleson drug abuse have appeared in the Encyclopedia Britannica, the American MedicalAssociation's Today's Health Guide, and the Yearbook of Substance Use and Abuse,of which I an} editor. For more than 25 yew's, I have been interviewing drugabusers ahout the substances they take, the contextin which they take them, and the gratificationswhich drugs provide. My interviews have ranged from experimentersto dysfunctional 124 120 abusers. In addition, I regularly track emergingsubitancei of abuse and monitor the degree of their popularity. the use of phenylpropanolamine in the For this reason, I have been folleWirig like to comment on its potential for Unites States for some years, and I would -- abuse. abuse, it must meet specific criteria: These For a substance to be a candidate forpsychological dependence that can lead to a criteria include physiological and/or compulsive desire for the Substance. Inaddition; substances of abuse can have dyS: functional effects on the user. Phenylpropanolamine does not meet thesecriteria. Phenylpropancilamino does not lead either _topsTchological or physiological dependence. It does not provide a "rush" or a"high. The body does not develop -a tolerance to it. It does not damage organsof the body; and it does not havesigmifi= cant dysfunctional effects. Certainly phenylpropanolamine is nota_drug of choice among drug abusers. It is not even a secondary drugof- choice for example as a subitittitefor amphetamine when the latter is not available.Indeed; the federal government's most recent report from its Drug AbuseWarning Network; for July-September1982, ranks phenylpropanolamine 102nd among drugmentions. Phenylpropanolamine accounts for less than one -fifth of one percent ofthe mentions. Nor did the government's most recentnational survey of patterns of drug abuse find phenylpepanolainine to be a dragof abuse. All the available data indicatethat phenylpropanolamine is unimportant in termsof both the incidence and prevalence of abuse. OccasicinallY, as you know; a particulardrug or combination of drugs has a group of users in one arealikeglutethimide and codeine 1"1-lits ") in theNewark area with a concentration of phenylpropanolamine now But there is no community conducted in users. In fact; at a nationalconference on epidemiology of drug abuse Rockville, Maryland; in December 1982with presentations from 19 major cities, not phenylpropanolamine as a substance beingabused. one presenter cited occasional The appearance of phenylpropanolaminein lists of drugs of abuSe or in anecdotal reports is likely to reflect oneof three things: (11 polydependent persons who aretaking many substances at the sametime, one of which is phenylpropanolamine; (2) users of "lobk alike" substances; or individuals (3) persons taking more than therecommended dose or hypersensitive with idosyncratic enemies. Epidemiological studies should be able toconfirm the role of polydependence,_ the accidental overdoses. In the case of the poly- decline of "look alikes;" and a drop in- it ac- dependent, a negative effect may beattributed_ to phenylpropanolamine when substances or from synergism among sUb- tually resulted from one of the other ephedrine- stances: Negative conseq_uences from"look alikea" usually stem from the component; caffeine and not from the phenylpropanolamine drop in Since this three-way combination is nowillegal, there should be a sharp this source. phenylpropanolarhine mentions attributable to appe- As the public has more experiencewith the use of phenylpropanolarnine in expect that the number of reportsof toxic reac- tite suppression, we can confidently substances tions will decline analogous to theexperience we have had with other which increased their popularity in a shortperiod of time On the subject of these reports of toxicreactions, I have reviewed a recently pub- Regional Poison Control Ceenter inUtah; lished report from the intermountain which Which raises some questions about theirValidity; The authors of the study, involved 70 patients who had takenoverdoSeS, either intentionally oraccidentally, of PPA-containing products stated: either the cases with only PPA orcombina- The lack of serious side effects in noted in ear- tions of PPA with caffeine raisesquestions about the serious reactions lier published reports."_ I am submitting a copy of this reportto the committee and ask thatit be included in the record (Exhibit that phenylpro- Speaking as a clinician, researcherand epidemiologist, _I lielieVe panolamine is trivial and insignificant as adrug of abuse and that it will become even less consequential in thefuture. Thank you 121

SCIENTIFIC REPORTS

Paperspablished in this section ere reviewed quirt leutemiqualified refew for accuracy. scientific soundness, experimental design, data analysis, and interpretation. Peons accepted may result from original rematch, critical liter ..... reviews or will documented COI Inwstigations.

WESTIOAT ic.v1F THE JOWJTv OF Nek-PEOLBIL'IlltI:1EL tlillboliith!a. aunt R fkins. Pharn 0 and Oilvld tpoerkel_.__Ir,_06.APh*__ intermoketein aeglon.l_Poisero_Coetrol C and Deportment-of- . h mmmm cy Practice. University of Utah. Solt Lake City. Uteh 64132 (Received June 18. 1081; Pavislon Roceived September 22. 10$2; Accepted November 12. 1913))

--The American compulsion to be elim;_com,_ Table 1.Commonly Matta le gmer-The,Counter_Stimm. bined vie)) ibe_Conclisiona_of-a-non-govern- lant.Containing Appetite Suppressant ment-advisory panel' recomsendations_in Products March of 1979 indicating teneocaine_end phsnylprogenolamine (PPA) in over-the- Product Manufacturer PPA Caffein* Other counter (OTC) weight_control products to_ (.0 (00 Sub. be_safe and effective, have increased the %tine. use and the availability of these drugs kn_Aserican_homes. - Height- controlproducts Move:tin obtained without prescription fall into Pick Your two el sympathontimetic-containing Menu Wight prodete and there without. Thane without UM Program may_contgin vitamins, methyleellutose, Anorexin SDA /harm 25 100 bentoexine, fructose, lethicin, and grapefruit extract. The eympAtbomimetie-contain- Anorexin SDA Pharm 50 200 ing weight control products may contain One-Span any of the above with PPA alone_or combined APPsdelne Thomson 25 100 with_caffeineTable 1 -lists some of the ari. Strength Medico! common commercially_ available products. %bile PPA_ii_reported-safe in doses for MOOress __North_ 26 100 weight control (1), there are limited data Tablets American

abOnt_the_texic_effects_of -PPA-mten taken Ayds Appetite Puree 25 0 io-overdose (2 -3). There is mounting evi- Suppresseet _ dence of serioue toxicity_when_taken-in Droplets (0.6 combination with other drugs (6-8) and m1°12 dropi) in hypersensitive persons_using_normal---- doses (9-20).Caffeine is not an innocuous Ayils_f.tra Pure. 75 200 drug (12,22). Although nerious_toxieily Strength frOm_eafieine_is_rare-, its danger is- well (sod Capsule) documented (23-28). Caffeine in combination Ayds -Ace /Pre Murex .mithLPPA,vall_contribute_to the toxicity Appetite Sup- /in possibly both overdosage and in regular doses. Peelaent Cap- sules Yallow_Cap. 50 200 The_purpose_Of_this_report_is_to_deseribe Blue Cap. 25 0 the range of-presenting-signs and sYmrtoms following ingestion of OTC sympathominetic- Celled. Cup- Central 75 200 COntaing weight--control products and to suits estimate the toxic dose and sequel,. from 'Codexin such overdose. Arco Phsirm 75 200 Coffee Break O'Connor 37.5 0 UET8ODS Cubes laelbrd Drub 1leduction Plan

The patients for_thls prospective-study Coffee-Off -Westport 25 were _either-children or adults who had Pharm Sales ingested a non,proprtelarii sympathomimetic- COntasnIng_setght-control product. The COVree._Tea. ThoopsOn 25 study period was for 5 month..Patienti and Now Me Medical men the follovIng-cr-tterla *ere included: Control Cap- History of ingestion of a sympathomimetic- lhomptee 75 sulem Medical Present address: Valley west Hospital. 4160 Mist 1400 SOuth. West Valley City. Utah 14020 Control-Drops/ Thompson 25 0.2 mtmi drops Medical vet Hum Youcol 16. 2Apr 1087 122

Table I(cant) Tab,. P (trot) PPR_ Caffeine Other Caffeine Other Product honufai rrrrr /redoes. nonalectirer IPA_ -Sub- (N) (.0) (n) (o) stances Stage. 25 0 4 Coal Dam idestpeint- 25 0 Fluides Plus O'Connor Tablets Pharm Sales Drug 60 0 e Soy Trle _ftiatmlips_ 75 Grapefruit Sharpe 'harm Sales Chewable Diet Rationale Tablets Weer° D.lco Tablets- 25 0 Grapefruit O'Connor 0 Cligeules 75 Dlet Plan Drug With_011odax Republic 50 200 Deis. -Oar Tablets tO Drug Capeules Capsule 30 Semadar Republic 75 200 Plus Drug Grspefrult O'Connell' 25 O'Cansar 75 200 Diet Plan Drug Capsules Drug 1010_151441x__ ffeireirlS_Dos- Cheiseble-Tab- lets Ex Smooth A-Olet 11) O'Conner 25 0 Grepefrult O'Conner 75 Drops ffoi,_ Drug .. 01.y Plan__ 0,40 array Des-A- Diet 11)70.6 el With Oladex Ei_Stretugh_Vin twin fortified SINTAOlet O'Conner 75 0 Contissuus Actium Ilia Cap- Drug Capsules sulas ___ Allegheny 25 0 Thompson 50 200 Swore* Ilmusetrle Phareocal Capsules Medical AllighinT 33.33 66 75 200 *inures Plus Oitotrin Cs PharmeGal Strength Tnidical CaPsules Obestat Seamen 75 0 Desitelm 0.1.1.1sa -Sea Super Odrinex Tmedi:r 75 Caffaine-Prsa Persethene.12 Alleotans 75 140 Ea- Strength Phonemes' Capsules N C Lab 7; 200 Oladae O'Conner Then99,0-75 Ex Strength Capsules Drug 50 0 Tablets 2$ 0 FAA 'Res Alleghaal 75 0 Strength INN...meal Oletac Pre. Donley 25 0 ilsal_Olet Aid Janes Labs Drops/0.2 el. Pro-Daa 21 0.Cafteir 73 _ _ D 5 droOs Drug . . - Oletac Pre- Menlo, 25 ._ e : ::. Tames Labs .. Real Diet AId Prolamine Thweancee 37.5 140 Tablets Capsules Medical _Manley__ SO 200 .. Malec 12 Sr J II 75 'I0 Nees Labs 'SD Appetite Dlet_Ald Control Cap- WIIIIIIims Capsules finale Illetsc-Max Nenley___ 25 0 James Labs INN_ADVetite J 0 Strength Suppressant IfIllisms - Capsules__ 25 0 Once-A-Day 75 0 Sip and Allegheny Tw1Ge-A-Oey 37.5 __O Slender Pharomeal 200 Dietcse l Perrigo 50 200 Slimplan Ex__ WhItsworth 75 Strength Plus Dieteap-with-L Perris., 75 0 45 out Caffeine Spantrol North 50 American __ DiAtquard 14 upitasall 25 0 150 4 gar Diet Plan Lab Sp Ex __North_ 75 American gist Trim ',harm. Present 0 Strength Amount? Plus 100 S-tiper OdrIneX r.. 25 ovii-sii:. Ul ulliallt_ toss 75 0 Phan...Gal Group Vet nun Tastes'21. 2 Apr 1983 123

Tea.' 1 (cant) Wile 2 Ss_ a list_of_the_non.proprietarY Product nenufecturerPPA Caffeine Other products involved in tho 70 cases. In some cases several products_were_involved. (.9) (.9) Sub- stance. Dexatrtmo (regular or-extra-strength) products accounted_ for 71.41 of All_the pro._ yhlea_Dropsy__ Alva Amp 25 0 ducts_involved-suggesting ready availability 0.2 1.5 drops Mammal In the homes from either advertising or sales success. Thimem4- Alm Awco 75 Toisture- Mumma' Tablet Leduc- Moth thisatrimm_products are-combinations lie_Plin ._ea___ of PPA and caffeine.Ten cases (14.3%) firmed. Mewl._ Involved only_PPA__the_remaining 00-cases (85.71)-involved combinations of both PPA Thina-Msn Alva Asco 75 . and caffeine in verying_doses_and_amounts- Na Strength Phermal No products with only caffeine were involved. Trim Own Aim Drug 75 0 __Noae-of-the-PPA-only cases involving_ Micro% Distthoublic 75 0 children under 14 developed eloptome_althangh - Plea Ciesulss prof mmall_amounte_were_generally-ingested. All of-the patients over 14 who ingoated tite_Silm Thompson SO 0 Capsules onlY PPA developed mild_symptoms.--The-- nedical symptoms described in these f011r patients_ 1711_10m- Porter/ma 25 25 included natieee,_vomitiag._abdominal_cramps. lag-Plan Sleuth headache.-bot flashes, diaphoresis, dyspnea. Tablet irritabilltv_and titebScardia_1140_44ate/min). In_patients-with-only PPA Involved, the containing !eight control product, stilmettuent onset of sylptoms was usually Y1141110_30 treatment,-follow-up or evaluation by the min_to_l hand the duration -of symptom' poisoncontrol canter ;toff or at a treatment averaged 13-b.Daly one patient required facility-All-ages-were included.- For hospitalization. An estimated-ingeeted patients evaluated and treated at Mee. dose in the symptomatic patients was 17.5 telephone - contact- was maintained to resolu- mg/kg. tion of symptoms or for twelve hour*, which- ever was longer.__Patiente were-excluded Me fixed dfniage ratios of PPA to caffeine from the study for the following reasons: (Table -1)- ranges from a low of 1:1 to Miestion_o_f_eignificent_mmunts of other high of 1:4. Therefore. _ at n given-dope drugs concomitant with the study drugs, of_PPA_the_ammunt-of caffeine present in lack of satisfactory history, and patients the product may vary by factor of four. whose condition was later determined to This_makes_defining_the _dosagen-of-elther be of another origin. PPA orcaffeine in combination difficult with the available_data.--Table-3-describe RESULTS symptomatic patients by age with the estimated Mist of PPA_and_caffeine_ingested_ During the five months of the study. and-the-dose to weight relationship. All. A totat_of_70 patients_met-the-criteria patients over age 13 were symptomatic_regard- of the study. The data from them patients less_of-the history of ingestion. Children form the basis of_this_report,-ThirtY- in the 0-21 y age range Renerallr took four percent of the patients were male Table 2.erands_of_diet_AidS Involved in Seventy (24) and_115:_eare fimale_3464 despite a Human PoimmOM mean-even Sex-ration in the 0-5 age group. The ages studied ranged from 9 m_tt, 20 brand Nara Ix 7-(mean _5.0 y,-SD w-5.74 y)-for males. and 11-54 y (mean 13.4 yi SD 12.1 y) for Appedrina /Minus Strength 1 1.4

female,. 1 Control 5 7.1 es -A-Diet 11 _Tbe Patients were divided_into_two_groups: 1 1 1.4 Those-involved with ac dentseh d Dexatrl 25 41.4 logestion_f9 m to 3,Y an t se .A0E:true- ecrillebstance abuse patients (age - Devatris Extra Strength 30.0 4 S WI WI! CIF4 Mx ratios of the Diem: 11.6 former_group were-near equal with no striking Pre-rwal Diet Aid Tablets differences. In the intentional grout: I naxime_Sirangth-Onm-A-Day 1 there is_e_110.3_ratio-of-males to-females Ire - /al Diet Aid Drops and a distribution Ot ages in females which 12 Hour Slat Aid indicates the mieuse of thete substances 3 4s not limited to a discrete age group. Hungres 1 1.4 The prePonderence_of females using- these Fermat:we-12 substances compared to males may be indica- 1 1.4 tive of the more likely purchaser of diet Phen-Pro-75 1.4 aids.- Young adults (age. 13-21 y) comprised Super Odrinex 30% of stl cams and almost 75% 01 the 1.4 x-It Intentional group. Children ages 0-5 ac- 2 2.5 counted for 50% of all c1141041 seen. Unknadn 1.4 Vet nun loxicol 25. 2 AO 190 44 124

tmesTradrtment end Dow, of Mien 1roanolamineCaffeine C. Tolle 3. 5 Ho Onset of Duration istbreted-Oose ingested 112iCec Ass total Symntometic (Ivan freataent Number (2) Symtami (hr) 89-18nwormorig-estlents __ hes ___ _Caffeine__ (hr) ---mNtk9 747 -7;Fri 40 9 10 2 2-4 133 10.5 460 0-2 19 3 (15,8) 500 94 7 11 ri 3 150 9.8 3-5 14 2 (14) 0 2 021 12 300 8.2 800 22 6 -12 2 1 (50) 8.8 1400 26 5 10 I 1219.48 575 11711 19 19 (100)_ 1 4 I/ 20114.5 235 5 6110 15 .22 7 6 (85J1 titration (201.__Common side effects from only 1-2 dbiage units. overdose associated-witb-PPA-include_hyperT tension (2,4.12-14.151SM), severo headaches Tbe type of symptomsand-frequency-noted in Table (2,4,11-15,19)s blurred vision_f15); donfa- In the study patients see lifted sion_14,,533,16,18,19), vomiting (2,12.19). 4-Headaches nausea or vomiting.-nervousness. and tachycardia_were most often seen. Almost and (seizures (2.5,13,20). within the first all symptoms appeared Ciffeine-ls_a naturally occurring alkaloid two-hours-__ In approximatelyone-third serious_ for_up Which is rarely associated with of the cases., symptoms-persisted adversereactions or fatalities (22). A to -6 -ham- another -one -third of the cases possible explanation for-the-low frequendk had symptoms. for up- to- 30- to 12 11_,and _ persist- of serious_reactione f111 the high incidenze the remaining one-thlrd had symptoms of_gastritis and prominent- central nervous ing for widely varying lengths of time. system tide_ effects with relatively small Pharmacologic affects On_the central Physician-evalUation_sus required only doses. :leventy-seven-percent nervous and digestive system can-be-seen-_ 16 time, (22.65%). with as little -a dose_as AO mg. A therapeu- Of the time-tne_Oroblem was managed at tie_dose is near 100-200 mg-(27).--Caffeine home with only demulcents-to-delay_absorption stimulates_the_cerebral cortex, the thalamus. Induction of em elt; using syrup orChe the vasomotor and respiratory-cen_ers_(21, of ipecac. Of the patients_managed_in_ 22,24-22)-___Cardiac stimulation resulting thehospital; only two requiredhospitaliza- from the emergency in a variety of arrhythmias_have_b.en report - tion, 64% were-discharged ed- 121.23.25)._ The combination of caffeine department.in less than 4 h, and-theremain- 8.25h, with PPA produces a_pharmacologid sYnergism ing dtscharged-in_an-amerhge of accentuating some action of each drug: lba_duration of treatment in the-health performed care facility-and_the therapy The dose at which symptoms developed ire noted in Table 5. for PPA alone-was 17-5_mg/kg. This is not suggestive of a minimum-toxic-dose. DISCUSSION rather-a dose-that predictably produced symptoms in the study patients.--then -PPA/ Phenylpropanolamine_is_a sympathodimetic to-amphetamtne,--- caffeine combinations were involved in- nine structurally similar children (a211-0-5),-a toxic-dose_for PPA_ The Oharmactlogfc dose sphedrine-and-metnrimitiol, as-a-direct was close_to 10_mg/kg (average total actions of PPA are described The caffeine_ddsci_averaged alpha adrenergic_effett and anindirect was 140 mg). 37_mg/kg with an ge total dose-of acting amine producingrelease -of norepine- endings 480 ing-producing-symptoms.__All adults phrine from storage site at nerve studied were symptomatic, su ggggg ing that (5,11). Its structural_formula_protects early-demo aaaaa ble_cIihical findings are it-from rapid degradation allowingfor from oral admini- expected and that symptoms are not-a_gOod extended duration of action early deseriminator betillten the low versus the high end of tonicity. r5e.yototovorequency Time No Table 5. Treatment-Perfotwed_and Duration Of Unlace in the /belch Care Facility (barber) (alerabssJmore than one symptom per use) Duration offing In the 20 health Care Facility (h.) Haute& or vomiting 12 <4- 9 fierreasness ID 478 4 headache a 8-14 14cDFCardio 6 2 Dizziness 014 3 gromsiness 3 Treatment PerforreO WeatineSS 2 Disorientation 2 Ipecac 9 Sbortneff_Of breath 5 1 ActivatedCharcoal Not flashes 1 Cathartic__ in, ..... d urination 4ntrarrnous_tydrAtipo Flushed- __ 1hen-o-Nabital Momoness of hands Vet Hun Ton;001 25. 2 Apr 1953 125

The 1r,ek of serious side effects in either Sr Med J 1:193, 1965. the Calle,. wish only PPA or combinations of-PPA-wish caffeine raises questions shout 5 NorytniasC, Widerlev E. Lonnerholm_d: Phenyl. the serious reactions nosed ln earlier propanolamine end mental disturbances. Lancet published_reports.The Bureau of Drugw/FDA 2:1367-1368. 1979. is currently preparing a report on Serious 6. OthbertAlf,_Greentierg_NP, Morley_SWi Cough -and morbidity_and_mortality-assocasted with- cold remedies: a potential danger to patients diet pills containing PPA, caffeine; and on monoamine oxidise inhibitors. Or ned J I: ephedrine. siagly_or_in combination wish 404.406.-1969- each other (Wawa= RE: Personal Communica- 7. McLaren EH: Severe hypertension produced by time. _FDA. Fehruary_19112). The_discrepancy Intrectionof phenylpropenolamlne with methyldopa in-the eeverit. f reactions in the FDA and oxpreno101. Brit Med J 2:283-284, 1976. rePort_ated the_current_study suggests-m*1,Y- 8. Lee KT, leilin LJ, Vandongen R: questiotts.--The incidence of such reactions, Severe Nyperten- slon_after_Ingestion of_ an appetlte-Supp Moir wwolutoillos of action_ and_ the true (phnyipropenolsminel with indomeShiCln. hazard-to-the community from such products lancet remains to be addressed. I (6125):1110.1111. 1979. reterson_1111ifacquer LA.-Phenyl-unopened-amine-- popularity of OTC diet aids will induced arrhythmia'. JAmA 223(3)024-325. 1973. likely_continue_to_produce_significant *0. Sees, F,_f _ St. Steufe CC4_ Allergy to ___ numbers of Ingestions, both accidente__ phenylpropanolemine. tied leteetlosal.___The results_of_th's-study_ Annals Allergy 40(0:32-34, tidiest* the majority of overdoses involving 1978. OTC diet aids will not be serious and may 11. Morowitz JO. MC0011 JJ. _Swat IL. et -a1:_ Hyper- 001y-require-decontamination-of the digestive tension and postural-hypotension Induced by tract and supportive care. We recommend phenylprosano1emini (Trleolets). Had J Aust 1: that_eamsis_Winduced-with-reported ingestions of diet aids involving more than 12.Sennett VII: Hazards of the appetite supp ssssss t 8-10 mg of PPA in children- Deliberate phenylpropenolamine. Lancet 2 (8132).42-43, 1979. I ***** ions-by adults require careful cons!- 13.Deocmoo_RO"_ COAWISIve seizures- due -to phenyl. theratioh_01 the history_of_ingestion" the propnolmine.J Had Soo NJ 76;591.592; 1979. agents-involved, and the intent of the victim. In mostcsae;_stmesisls should be Induced King J: Fhl.rtengian end cerebral hemorrhage in-all adult poisonings unless there is after trimolets ingestion. Had J Aust 2:258. strong evidence not to. In children a 1979. dose-of 11-10 mglitg-would be expected to 15.Korowltz_JO,_Lang WJ,_Howes_LC. et al: _Wyperten._ produce only mild symptoms' however, the tive responses by phenylpropanolamine in anorectic fiPset_and_trauma of forced emesis-is con- and_decongestant preparations. Lancet I (2159): sidered leas hazardous and preferable to 60.61, 1980. allowing a victim _to_devolop_even-raild___ 16.Schaffer CB. Pauli 11W: Psychotic reaction caused symptoms. The use of this dose as a cut- by proprietary oral diet agentS. Am J Psychlat Off for the Induction_of_emesis_is_consistent 137:1256-1257. 1980. with-our clinical impression that amounts of PPA below ;his quantity are well tolerated 17.bleu Al: Amphetamine-like reactions to chenil. and -are not expected to-result-in any more propanolamine. JAM245:601.602. 1081. serious side effects. ObviouS1Y; if the 18.SOW A84 Wein itDiet Olds. Mate; toe affec- bistory_of_ingestion-cannot reliably be tive illness. AA J Psychlat 138:392, 1901. ascertained shou10 be PerfOrMed. Physicians -and poison control- centers should 19.Elliott Cf, Whyte JC: Phenylpropanolamine and recognize that these agents can produce___ hypertension. Had J Ault 1:715, 1981. Ille,th *** t * ning_cardiac_arrhytheiss, hyper- 20.ilernsteln-E.-Olskant_1111:__Phenylprnpanolemine: tension, and other aerious effects. Tally_ hatardous drug.Ann (mere Med 11: )11,315, 1982. -The challenge-to pharmacists and physicians 21.Turner JE, Craver RN: A fatal ingestion of is to educate the eonsUMitle_Oublic to_the caffeine. Clln tax 10(33:341-344, 1977. safety_aed proper-use of-these and-other 22. substances for weight reduction. Treatment McSee_Mit- Caffeine poisoning in -19-yeer old of serious adverse reactions- or- overdosage female. J forensic Sci 25(1):29-32, 1980. with OTC diet aids will continue to be 23.Josephsongw,_Stine RJ:_ Caffeine intoxication: a_Clinical problem_as_long_as_the_public cos, of paroxysmal atrial tachycardia.JACO demand for this method of weight control 5:776-778; i976: remains constant. 24.Sullivan_ JL: Caffeine poi-seining in an infant. J Peels 9016):1022-1023, 1977. REFERENCES 25.Rulkars; PI, Oorind RD;Caffeine toxicity in a neonate. I. Anon: The new diet pills. Consumer Reports 1: Pediatrics 64(2).254-255, 1979. 1-4.16, 4982. 26.Shen W, D.Soute TC: Cola-induced psycotic or- 2. Patterson fx: Delayed fatal oJtcome of after genie brain syndrome. Rocky lit Med J 76(63:312- myyible Sy-toss: uverdose. J Forens;C SC; 25: 373, 1979.- 5,5.552. 1924. 27.0 _ ftih ea, _Arute_raffelne_overdose Jn 3. Duffy O. Sone4iln_h0.__Knight Tr. el al:Acute the neonate. Am J Dis Child 134:495-498. 1950. renal- failure due-to phenylpropanolanine. South Had J 24:1548.1549. 1951. 28. May DC. Long T. Madden R. et al: Caffeine taxi city secondarY_to street drug ingestion.Ann 4. Salmon Pil: Hypertensive crisis with EsSornade. Exu.g Me10:549. 1981.

vet mum Toxicol 25.2 Apr 1933 41N

27-436 0 - 84 - 9 126 Dr. SILVERMAN-. Thank you; Dr. Wmick. The next colleague to contribute is Dr. Noble from California, and from the University of California Hospital in San Francisco. Dr: Noble? STATEMENT OF RUDOLF NOBLE Dr: NOBLE: My name is Dr. Rudolf Noble. I hold both_ an M.D. degree and a dbctorate in organic chemistry. Currently I am a clinical instructor in medicine at the University of California Hos= pital_in San Francisco and I am director of the Cathedral HillObe- sity Clinic in the same city. I have with me written testimony that I have asked to be entered into the record. However, these_ are the important points of that testimony. I have recently conducted a study of both the medical andpsyi. chological _safetY of Phenylpropanolamine._This double blind study involved 216 patioats and is part of a four-city; 864 on-going patient study. We have analyzed the medical data on my part of the study, that is to saY, the 216 patients, and I can report to youthat we found significant changes inblood pressure or pulse rate whether the patients took a time-release 75milligram dose Of PPA or took a 25 milligram of PPA three times a day, as compared tothe placebb group. In addition; the psychological profile that we conducted Ohthese patients indicated that PPA had no significant effect on mood: M I wrote in apublication in the June 1982 issue ofLancetand here _I'd like to mention that that is not such a badmedical journal, Dr. RameyanyWay,_as I _published in that journalbefore doing the study, in the past 2 years I- have done threelarge studies in our obesity clinic involving more than 400 obese_patients onthe effect, over a period Of 12 weeks_,_of 3 different dose formsof PPA. Our results confirmed; even before my latest studythat I just told you about; that PPA does not cause a significantincrease in bloodpressure,_even in doses up to 150 milligrams: In addition, I studied 60 patients who were giveneither PPA or an appetite-curbing inedicationavailable only by prescription: The weight loss was the same in both groups, In my view; from my studies; PPA IS a safe andeffective_over- the-counter appetite suppressant for the millions ofpeople in this country WhO want to lose weight. Thank you verymuch. [The prepared statement of Dr. Noble followsj PREPARED STATEMENT OF-RUDOLF E. NOBLE, M.D., PH-D., DIRECTOR OFCATHEDRAL HILL OBESITY CLINIC, SAN FRANCISCO, CALIF. Good morning. My name is Dr. Rudolf Noble. I hold a Dectorate inOrganic-Chem- istry from the University of Colorado at Boulder and an M.D.degree from Western Reserve University. I have been a Fulbright Post-Doctoral Research Fellow at_theUniversity of Hei- delberg in Germany; a Research Fellow in Medicine at Western ReserveUniversity and at the Univeriity of California Hospital in San Francisco,where I did my internship in medicine. I didmyresidency in medicine at Stanford Hospital. Currently I am clinical instructor in medicine at the Universityof California Hospital in San Francisco and director of the Cathedral HillObesity Clinic in the same City. After the FDA Advisory Review Panel in 1979 pronouncedphenylpropanolamine (PPA) to be both safe and effective,there have been sporadic reportsthrowing some doubt on that finding. Certainly; as director of the CathedralHill Obesity Clinic, I

1 3I 127 am very concerned with t he safety and effectiveness of OTC drugs used as appetite suppressants. I am often asked about these medicaments by patients and I might b-e held liable for any given advice. Accordingly, I and others have been conducting new studies testing the safety of PPA. In a significant; large-scale study I have recently conducted; we_ looked at 216 patients for both the medic_and psychological safety of PPA at different dose levels compared with a placebo. Of these 216, 36 were of normal weight; 72 were 15-30 percent overweight; 72 were 31-45 percent overweight and 36 were more than 46 percent (or severely) overweight. The study has just been completed. Patients were studied during a 12-hour period. Patients took a 75 mg time-release dose at approximately 8 A.M. and a placeboat approximately noon- and 4 P.M. A second group took 25 mg at those times. A third group received a placebo at those three times. Patients were checked for blood pressure and pulse rate (both standing and lying down) on administration of the drug and at one-half hour, 1 hour, 2 hours; 4 hours; 41/2 hours; 6 hours; 8 hours; 81/2 hours; 10 hours and 12 hours afterward& In addition, clinical measures of subjectit e emotional s:.ites were obtained using self- administered standardized mood-scales at each of the 11 measurement intervals. analyzing the clinical dataI can report to you that PPA at the 75 mg_ dose level causes no significant change in blood pressure or pulse rate. An analysis of the psychological mood-scale data also showed no significant changes in emotional state: There was an incident that you should know about.-One patient went home and later called in to report that she was hallucinating. Under our emergency procedures, we broke the seal on the medication she had been taking only to discover that at each medication time that day, she had been taking the placebo. This study is one phase of a four -phase study. The same study is being replicated for 216 patient groups in Seattle, New York and Beaton. What do I think about PPA? Let ine summarize what I wrote in a letter that was published in June 1982 in The Lancet prior to undertaking the study I've just described. (Exhibit A) To quote parts of that letter: "In the past two years, I have done three large studies- in -our obesity- clinic in San Francisco of the effects of three dosage forms of PPA. More than 400 obese patients were studied. "Data were gathered on a twelve-week, double-blind, placebo controlled study of 50 mg PPA three times daily (twice the recommended dose for weight loss); a double-blind placebo controlled study of 50 mg PPA combined with 200 mg caffeine in controlled-release form; and a single-blind trial of 75 mg PPA in controlled-release form. "Our results confirm that PPA does not cause a significant increase in blood pressure even when the amount ingested (150 mg/day) is substantially higher than the recommended 75 mg dose. There was; on the contrary; a reduction in blood pressure as-the studies progressed." My acute and chronic studies subsequently show, ladies and gentlemen, that PPA is a safe and effective appetite suppressant for millions of people in this country who want or need to lose weight. Thank you 128

Noble, R. E., Exhibit

A. Phenylpropanolamine and Blood Pressure, The Lancet, June 19, 1982

PREVYIPROPANOIJVANE AID BLOOD PRESSURE Sth;Altbouthphen_yloropanolarnine(PPAlhas been safely used in the U.S.A. for over forty years as a nasal decootestint, your April 10 editorial raised the possibility that PPA in weight control preparations could produce increased 51 pressure. past two yam! Wee done_tthee_Grtestullmtn ourobetity cttcic itiSanirketiaca ofthe_effectkolthres_dosate fornsto_f_PPA. More thui OIX obese patients were studied. The results will be published elsewhere. Dorawereptheredon tare week,double.blind, pLuebo controlled study _of 50 ng PPAree- -tie _ (twice the recommended dose for weigh :-Loss A doubletblind; plembo study of 50 mt PPA combined with 200 mg caffeine in controlled. release form; and a single-blind trial of 75 mg PPA in controlledrelease form. All three dosages mused no significant incease-in blood pressure in more tn 400 patents. 2 patients experienced noteworthy rises sis_hlrosd pressure Alter_ trestment.ida 75 mg PPA; but these increasm were felt not to be drug related. The mean pooled systolic and diastolic blood pressure in the 50 Mg x 3 PPA, placebo study are shown in the figure. Our results confirm that PPA does nor causes sividicant immense pressure even when the amount ingested_(150 itsWay) subitannIllyinglier than theiscornmended T.Stogclose. W33:, onthtcootrary, a reduction in blood pressure as the studs progressed. Cathedrslfidl-Obwry San Enonsm.Caidanust4101. S.A RthsoLl, E. None

toasts .

stun.alt to

r. n4,1

r Ploctu:. 8P

Mena oystolie and dLiatelie bleed pressure.

133 129 Ms. OAKAR. Thank you, Doctor. Dr. SILVERMAN. Thank you, Dr. Noble. Next we will hear from Dr. Conte. Dr. Conte is an internist who practices in Beaver; Pa:, and specializes in the treatment, of the obese. Dr. Conte? STATEMENT OF DR. ANTHONY CONTE Dr. CONTE. My_ name is Dr. Anthony Conte. I am a bariatrician, who is a physician who- specializes in the medical management of weight control. I have been in private practice for more than 20 years in Beaver, Pa., where I direct a clinic for obese patients and I'm proud to say that -I treat patients; not scales; I have brought with me written testimony that I request be entered into the record. Ms. OAKAR. Without objection. Dr. CONTE. I wanted_ to share with you the important points of that testimony. Over the past 7 years I have_prescribed or recommended phenylpropanolamine to approximately 7;000 obese patients, including patients with elevated blood pressure. I can tell you that I've never observed any adverse side reactions in the patients. On the contrary; _I have found PPA to be a valuable adjunct in the treatment of obesity. In published studies that my colleague and I have done comparing the safety and effectiveness of PPA against a placebo and against appetite suppressants available by prescriptions only, I have found PPA to be equally effective as prescription drugs and far more effective than placebos in helping patients lose weight. I have not found any significant side effeceffects;,changes in blood pressure, during and after several months of use In short, phenylpropanolamine is, in my view; a safe andeffective product which; when used as directed, offers help to the 80 million Americans who need to lose weight for the sake of their health and well-being. Thank you. [The prepared statement of Dr. Conte follows:]

PREPARED STATEMENT OF ANTHONY CONTE, M.D., BARIATRIC1AN, BEAVER; PA. GOOd morning. My name is Anthony Conte. I am a physician with a specialty in bariatricsthe treatment of obesity. I have been in private practice for more than 20 years in Beaver, Pennsylvania, where I direct a clinic for obsese patients, and am an attending physician at the Medical Center a Beaver County. I received my-MD degree from the University of Buffalo School of Medicinein_Buffalo, New York in law. From 1957-64; I was the Director of Anesthesiology at both Beaver Valley General-Hospital in New Brighton, Pennsylvania; and Providence Hospital, in Ekaver Falls, Pennsylvania. I was invited to participate in the 1969 White House Conference on Nutrition. I am currently a nutrition consultant for the University of Pittsburgh Department of Athletics. Over the past 20 years, I have treated more than 25,000 patients suffering from obesitya healthAhreatening condition affecting 80 million.people in this country. I have observed patients who are desperately trying to_lose weight, trying to change eating_habits that had been followed for a lifetime. And, I have seen patients leave my office 20 or more pounds lighter than when they first consulted with me. In my obesity clinics, my treatment method varies with each patient But one of the more consistently effective treatments, which offers help to a broad segment of obese patients, has been the use of phenylpropanolamine to suppress the appetite and make it easier for patients to cut down their caloric intake. OVer the past seven years, I have prescribed or recommended PPA to aproximately 7,000 patients, including patients with elevated blood pressure. I can tell you that I have never ob- 130 served any adverse side effects in these patients. I have found PPA to be a valuable adjunct in treating obesity. Befbre any patieht begins treatment with me; he or she undergoes a complete physical examination, a series of blood tests, a nutritional evaluation; an electrocar- diogram, and an evaluation of the status of the cardiac, kidney and liver systems. In follow-up visits, which take place at least once a month, the patient'S Weight, blood pressure and pulse are checked. Part of my professional practice also includes carrying out scientifically controlled studies to measure the effectiveness -of various methods in treating obesity. I have reported my findings at meetings and symposia of the American Society of Bariattic Physicians and the International Academy of Preventive Medicine. I have published papers in the International Journal of Obesity and in Obesity_and BariatricMedi= cine, the journal of the American Society o:Bariatric Physicians. I have also carried out research studies for various pharmaceutical companies, including A: H.Robins; Sandoz, Smith, Kline and French, and Thompson Medical. I'd like to review some key findings of some of my research that relate to the Sub= ject of today's hearing. In an article published in 1982 in the International Journal of Obesity, I reported with other investigators on research we carried out which studied the use of a phenylpropanolamine-caffeine combination in overweight patients. 201 patients were studied to compare the safety and efficacy of PPA against a placebo and againSt Ma: iindol and diethylpropion; which are both appetite suppressants available by prescription only. Over a period of 6 weeks, patients taking PPA lost significantly more weight than those taking a placebo: 4.64 pounds compared to 2.07 pounds. And, -when we compared PPA to mazindol and diethylpropion,we found PPA to be equal to thoSe prod: ucts in helping patients lose weight. The effectiveness of PPA was clearlydemon- strated. Patients in this study were required to visit the physician every two weeks to be weighed, At each visit, blood pressure and pulse were recorded, and patients were asked about any side effects or adverse reactions. They also had to return any unused medication.- We found that patients taking PPA had fewer side_effects than patients on mazindol or diethylpropion.-In fact, in the PPA versus placebo group; two patients taking the placebo reported side effects: dry mouth, diuresisand itching. These reactions are often observed in people who are starting to diet and change their eating habits. In another study, I compared phenylpropanolamine with diethylpropion, an appetite suppressant available by prescription only. In a group of 48 patients, nosignifi- cant differences were seen in the amount of weight lost by patientstaking PPA as compared to diethylpropion. And, there were no clinical deviations in blood pressure or pulse in either group. my interpretation of the findings of these and other studies is that phenylpropan7 olamine is a Safe and effective product which, when- used as directed, offers help to the 80 million Americans who need to lose weight for the sake of their health and well-being. I intend to continue recommending it to my patients. I am submitting my comments, and a copy of the study I referred to, to beentered into the record. Thank you.

1 30 131

Conte, A., Exhibit

A. Altschuier, S,, Conte, A., Sebok, M., Marlin,R. Lund Winick, C., Three controlled trials of weight loss with phenyipropanolamine; International Journal of Obesity (1982) 6, 549-556

Internationaljournal of Obesity (1982) 549-556. Received 17 November, 1981: accepted 13 April; 1982:

Three controlled trials of weight loss with phenylpropanolamine

Stanley ALSCHULER, Anthony CONTE, Marianne SEBOK; Robert_[ , MARLIN-and Charles WINICK Medical Colhwe ofPennsylvania,Philadelphia, Pennsylvania 19129 and Veteran's Administration Hospital, Philadelphia; Pennsylvania 19104; 255_Third street; Beaver Fay, Pennsylvania 15010; John F. Kennedy Memorial lkipital, Philadelphia, Pennsylvania 19124; 8 Biscay Drive, Parsippany, New jersey 07054; (Sty University of New York Graduate Center; Ni' York; NY 10036; USA:

Summary A multisite double-blind study was designed to determine the effectiseness of a phenylpropanolarninc-caffeinc combination in achieving weight loss.1wo- hundred and one obese adult patients were divided into three separate groups in which phenylpropanolamine/caffeine was comparcd with either placebo (6 weeks), mazindol (6 weeks), or dicthylpropion (8_weeks). In these clinical trials; phenylpropanolamine /caffeine proved to be as effective as mazindol and diethylpropion andsignificantly more effective than placebo in achieving weight loss. Overall, phenylpropanolamincicaffeiric had fewer side cffcct-s than mazindol and diethylpropion. Its use as an effective anorectic agcnt in thc treatment of obesity is reviewed.

Introduction The substantial professional and consumer concern about obesity in America has led w a growing interest in appetite suppressants as substances For assisting people to lose weight. This is a report on :in integrated program of threecon- trolled studies on phcnylpropanolarnineicaffeine as an appetite suppressant. Phenylpropanolamine is a s_yinpathomitnetic drug which is a synthetic deri- vative of ephedrine. It is al3-phenethylamine with a methyl substitute on the 2 carbon and a hydroxyl group on the beta carbon, The latter substitution generally decreases CNS activity'. In rats4, and in monkeys°, phenyltiropanolathihe urbs food intake without overt signs of change in activity level. Caffeine hasno appetite suppression effect but is included because many patients on weight reduction regimens experience fatigue and lassitude, which the caffeine helps to counteract. 132

In the current double-blind studies conducted withco/TA/eight adults, there was a 6-week comparison of a placebo (Study -weeci.:°rnpanson against mazindol (Study II), and an 8weekcomparisonagainst thYlproPion (Study III).

Subjects and methods Subjects All study patients were between 18 and 65 yr old and frarn12 to 45percent overweight, as determined from the Metropolitan Life Itisur4rice tables.(Statis- tical Bulletin;40; 1; 1959 & 47, 1, 1966). The examining physiciarimeasured the patient. s heightto thenearest inch and weight to thc nearest Eound. The physician then evainater Patient's fraine as either smallonedium, or large. Taking thc midpoint desirable weight for thepatient'sheight and frame sizefrom the MetroP°: Lire Insurance Company tables, the degree of overweight in per cent etern'ined by the formula: actual weight desirableweighk100 --desirable weight No patient had any clinical disease or surgical coriditi°!lt\Atch niight interfere with the medication; no patient was pregnantor lac1A-,or-.adh participated in any weight reduction program for atleast3 weeks .Preceding the study. Informed consent was obtained in writing from allpatierlb'0The Patients,re. cruited from the physician's private practice, were told°ttt the Procedures and goals of thc study. At the first session, a history of each patient wastakesp 0a PhYsical examination conducted. Patients were required to appearevert!.- thereafter, to beinterviewed and weighed by the physician. At each vi5 t' Noodblood Pressure and pulse were measured and the patients were asked to rePQt,r,.'llY side effects or adverse reactions and return all unused medication. All l'"" NY data collection were carried out with similar case report forms. If a patient reported any side effects or reactions,the_Physician-obtainedfull on- the patient's record. details; evaluated their significance, and recorded themor reactions The physician also recorded the absence of such ,ifects ;when appropriate. siii In each of the three studies, patients wererandomlyof°"5tr.lied to one of two groups, which were essentially homogenous in terms NI criteria -Each experimental group received either a placebo or pnetlY1Pr.c.,4riolanline 37.5 mg, 140 mg caffeine_(sustaincd release)* b.i.d. (Study 1), rn0,!2:4112m phenylpropanolamme 50 mg and 200 mg caffeine (sustainedrelease) **()nee a day (Study II), or dicthylpropion 25 mg or phenylpropan°113M,...t 25 mg, 100 mg caffeine** t.i.d. (StudyIII).The substances being identically- appearing capsules. In each of the three studies, theccmiPall.tNefwpehreeritnylpropano- Arnr/aft lamine contained in the capsule was different, so that thefrequencyofingestion

4 vat/able coramesciallY as Prolamine: **Available comm?reiallyfsm)Notrisnt...Available commercially as Appedrine: all products distributed by ThodsPso" ettiaal Company, 1 New York, NY 10022.

137 133 was different, as noted above. Patients in Study I were not required to follow a specific diet but were encouraged to follow sound nutritional principles. How- ever, all patients in Studies II and III were provided with a balanced 1250 calorie (5.23 NU) diet, along with instructions on its use. All patients were seen every other week and all data were entered on similar case report forms. Procedures Study 1.Stlicly I followed a double-blind comparison of a placebo (lactose) against 37:5 mg_phenylpropanolanine with 140 mg of caffeine; in a sustained action capsule. The patients took either test medication daily at 1000 h and 1600 h for 6 weeks and were given no specific diet. There were 72 patients. Mean initial weight for the medicated patients was 161 I:. (73 kg) with a range from 131 to 203 lb (60-92 kg). Mean initial weight for the placebo patients was 162 lb (74 kg), with a range from 118 ti 205 lb (54-93 kg). The medicated group included six males and 22 females; there were nine males and 19 females in the placebo group.

Studyff. Study II consisted of a comparison of 50 mg of phenylpropanolamine with 200 mg caffeine, against 2 mg of mazindol, an imadazoisoiridole anorexiant in the Drug Enforcement Administration's Schedule III, which has been found to he superior to placebo as an appetite suppressant3.". The patients took either medication once daily at 1.000 h, for 6 weeks and were given a 1250 calorie (5.23 NU) nutritionally balanced diet. There were 67 patients entered (58 female, nine male). Mean initial weight for the mazindol patients was 169 lb (74 kg), with a range from 122 to 240 lb (55-109 kg). Mean initial weight for the phenylpropanolamine patients was 1701b (77 kg), with a range from 118 to 240 lb (54-109 kg). The mazindol group included five males and 23 females; there were three males and 24 females in the phenylpropanolamine group. Study/H. Study 111 compared 25 mg of phenylpropanolamme with 100 mg caffeine and multi-vitamins, against diethylpropion, a phenethylamine anorexi7 ant in the Drug Enforcement Administration's Schedule ill; which was found to he clinically effective in achieving weight reduction". Either medication was taken three times daily, 30 min before each meal, over 8 weeks, with a 1250 calorie (5.23 NIJ) nutritionally balanced diet. There were 62 patients (59 female, three male). Mean initial weight for the phenylpropanolamine/caffeme/vitamins group was 161 16 _(73 kg), with a range from 120 to 219 lb (55-100 kg). Mean initial weight for the diethylpropion group was 160 lb (73 kg), with a range from 129 to 196 lb (59-89 kg). The phenylpropanolamme group included one male and 24 females; there was one male and 22 females in the diethylpropion group. (Numbers within groups signify patients who completed the study). Results Stiidy1 The mean and standard deviation of the cumulative weight loss occurring at weeks 2, 4, and 6 are set forth in -Table 1. Phenylpropanolamine was consistently associated with more weight loss than the placebo; the difference, as measured by Student's t-test and analysis of variance, was not statistically signifi- Table 1, Comparison of weight loss achieved by phanylpropanolamina vs placebo, muindol and diethylpropion at 2.week interval'

Change in body weight from baseline

Medication Baseline to 2 weeks Baseline to 4 weeks Baseline to 6 week Bue line to 8 weeks

Study L Phenylpropanolamine vs placebo

lb kg Le, kg lb kg s.e. t kg lb kg Le, t kg

Phenylpropanol aminolcaffeine 3.07 129 0A9022 -3,711,68 0.60 0.27 464 2,10 0.72 0,32

In 281

Placebo (a28) :1,96 0,89 0,400.18 :1,68 0,76 0,62 028 2,07 0,94 0,69 0.31

Study II, Phenylpropanolemine vs rnuindol

lb kg s,e. t kg lb kg Le; t kg lb kg see, t kg

Phenylpropanol. aminekaffeine 4221.91 0,68 0205,142.60 0,73 0.33-8.113,68 1.02 046

In 271

Mazindol 281 4.502.04 0,57 0256532.96 0.660309,004,08 0,790,35

Study 111, Phenylpropanolamine vs diethylpropion

lb kg Le. t kg lb kg Le, kg lb kg s,e. t kg lb kg s,e, t kg

Phenylpropanbl. amineWaffeine 3401,54 047021-4.922230;60 0275,672,57 0,80 0,36-6;843;10 0250;38 0:251

Oietkiyipropion -4;041.83 0;61 027-5212;54 0;860,396213;00 1;17 053 7263.61 1.44 025

231

13 135 cant at week 2 but was significant at week 4 (P < 0.02) and week 6 IP < 0.01). The approximately 2:1 ratio of weight loss achieved by patients _on phenylpropanolamine as compared to those on placebo, is consistent with the results of a review of pooled studies involving 7000 patients who were taking prescription anorectic drugs compared to placebo; over a variety of timeintervals13. Four patients on phenylpropauolamtne reported adverse reactions: dry mouth, diuresis; diarrhea; and constipation. One placebo-treated patient experienced dry mouth and diuresis and another cited itching. The reactions, which occurred only during the first 2 weeks, are not uncommon inpersons starting weight reduction programs and changing their _food intake_patterns. Blood pressure_ and pulse readings were taken at each visit. The means for each arc reported in Table 2. Of the eight patients using_phenylpropanolamine who dropped out of the study; live could not keep appointments; one had no transportation; another experienced nausea, and one was terminated by his family physician. These reasons were determined, in this and the other studies, by follow-up calls to the patients. Of the eight patients on placebo who dropped out; five could not keep appointments, one experienced nausea, another had no transportation, and one was terminated by her family physician.

Table 2. Diastolic and systolic pressure and pulse at beginning and end of study

Diastolic (mmHg) Systolic (mmHg) Pulse (beats /min) beginning end beginning end beginning end Study I(6 week evaluation) Phenylpropanolamine/caffeine b.i.d. (n =28) mean -78.9- 78.1 124.4 1244 73.4 72.9 range 70-90 65-90 110-150110-15068-82 68-82 Placebo b.i.d. (n = 28) mean 84,3 822 128.3 127.7 742 73.5 range 65-90 70-100110-150110-15064-88 70-88

Study!! (6 week evaluation) Mazindol o.d. (n = 28) mean 79.3 75.9 120.6 1182 76.4 75.2 range 58-94 54-88 108-146102-13864-90 66-96 Phenylpropanolamine/caffeine b.i.d. In 27) mean _76.6 _76.6 115.6 1_17.4 75.3 74.3 range 60-90 62-86 90-142 96-150 60-90 60-86

Study HI (8 week evaluation) Diethylpropion t.i.d. In = 23) mean 71.4 72.0 1112 113.5 77.2 783 range 60-80 60-82 94-130100-14062-88 72-100 Phenylpropanolaminp/caffeine/ vitamins In = 25) mean 69.9 70.1 110.8 112.8 78.1 78.8 range 54-82 58-88 98-126 96=140 60-100 68-88

140 136

Study 11. The mean and standard deviation of the cumulative_ weight loss occurring at weeks 2,4 and 6 are summarized in Table 1. M each measuring point, as meas- red by Student's t.test and analysis of variance, there was no significant difference between phenylpropanolamine and mazind JI in terms of weight loss. None of the phenylpropanolamine patients reported any side effects but seven mazindol patients did so (P < 0,05). These included: constipation (2), dry mouth (2), nervousness (1), hot flushes (1), lightheadedness (I). Blood Ares- sure _and pulse readings were taken at each visit and the means are reported in Table 2. Six patients treated with phenylpropanolamine gave no specific reason for dropping out, one did because he was not losing weight. Of five patients treated with mazindol who dropped out, two gave no reason; one became irritable, another had a dispute with her husband, and one was not losing weight.

Study 111 Table 1 sets forth the mean and standard deviation of the cumulative weight loss of the phenylpropanolamine and diethylpropion group, at weeks 2,4,6, and 8. There was no significant difference between the two groups, at any point of measurement, as measured by Student's t-test and analysis of variance. Five patients treated with phenylpropanolamine experienced side effects: dry mouth (2), headache (1), nervousness (1) and cramps (1). Seven patients treated with diethylpropion experienced: headache (2), nervousness (2j, cramps (I); insomnia ( I), and too much energy (1). Blood pressure and pulse measurements were taken at each visit and the mean cases are reported in Table 2. Six patients treated with phenylpropanolamine dropped out because of: schedule conflicts (2), lightheadedness (1), moving away (I), discouragement (1) and a broken leg (I). Eight patients treated with dicthylpropion dropped out for various reasons: couldn't keep appointments (2), not effective enough (2), schedule conflicts (I), nervousness (I), stomach cramps (I) and no specific reason (1).

Discussion A number of earlier studies have suggested the possible utility of phenylpropanolamine as an adjunct to the treatment of obesity". Phenylpropanolamine's appetite suppresant effect is well established and recognized by the US Phatmo- copeia Convention'. Its use for this purpose has assumed additional relevance because of the growing concern over the use of amphetamines in the treatment of obesity. Amphetamines have actually been barred for such purposes in England (1968), Sweden (1970) and Canada 11972). Phenylpropanolamine's abuse potential is practically non-existent% as is its tolerance potential's. A previous report raised questions about the safety of phenylpropanolamine in achieving weight loss". This report, however, was based on experience utilizing dosages larger than those employed in the United States. However, in a study of 37 adults, it was found that phenylpropanolamine (25 mg) by itself in combination with caffeine (100 mg) had no significant effect on either systolic or diastolic blood pressure measured at intervals over a 4-h period's. As set forth in Table 2, phenylpropanolamine has minimal negative cardiovascular impact.

141 187

In.one double-blind crossover study, phertylpropanolarnine reduced body weight significantly more than a placebo, without noticeable stimulatory side effectsl!. Another previous double-blind study, in which the patients had been given a nutritionally balanced diet had found phenylpropano/aminc to be superior, to a statistically significant degree, to a placebo in achieving weight loss'. Similar results were achieved in the current investigation (Study I), in which the patients were advised to use good nutritional judgment, but were not given aformal diet. It was felt that not providing the patients with a specific diet would add an additional dimension to the investigation. Thc current study also implements the suggestion of an experienced bariatric physician that clinical assessments of anorectic drugs employ more than one dosage level'. In the current study, three different dosage levels were used, as well as different settings: a general hospital, Veterans Administration hospital, and a private office. Thc hospitals are located in a large city (Philadelphia), and the private practice in a suburban community in the same state. On the basis of previous findings and of the current study, phenylpropanolamine would appear to merit consideration as an anorectic agent of choice based on its efficacy, safety, and lack of abuse potetitial.

References in 1 Asher; W.L. (1976):A clinical assessment ofanorectic drugs. InConference on obesity perspective, ed G,A, Bray; pp. 445-448. Bethesda (MD): Government Printing Office DIIEW_NIII 764352. 2Bray, GA, (1976):The obese potient,_pp.179-380. Philadelphia: W.B. Saunders. 3GOlitt;A. (1973): Evaluation of Sanorex a new appetite suppressant.Obesity/Bariatrw Med:2. 104-107, 4 Epstein. S.N. (1959): Suppression of eating and drinking by amphetamine and other drugs in nzlinal and h_yperphagic rats./Comp. Physiol. Psycho/.52, 37-45. 5 Goodman.L.S. & Gilman, A.I1965):The pharmacological basis of therapeutics, 5th edn, pp.478486. New York: Macmillan. 6Griboff, S.1, Berman, R. & Silverman, H.I. (1975): A double-blind clinical evaluation of a phenylpropanolamlne-caffeine-vitamin combination and a placebo in the treatmentof exogenous obesity.Cure Then Res.17, 535-553. 7 Griffiths, R.R., Brady, J.V. & Snell, J.D. (1978): Relationship between anorectic and reinforcing properties of appetite suppressant drugs:implicationsfor assessment of abuse liability.Biol. Psych.13, 283-290. 8Hamilton, C. (1977): Phenylpropanolamine as anappetite suppressantin monkeys; unpublished paper. 9Hirsch, LS. (1940): Reducing appetite in treating obesity.Ohio State Med. J.36; 742- 743. 10Hoebel, B.G., Krauss, 1.K.. Cooper,J. & Willard, D. (1975):Bodyweight decreased in humans by phenylpropanolattune takenbefore meals. Obesiryjnariatric Med.4,200-206. 11 Horowitz,J,D., Howes. Christophidis; N.;Lang; Wj,,Fenness_y, Md. & Louis. Wj. (1980): Hypertensiveresponsesinduced by phenylpropanolamine in. anorectic anddecongestant preparations,Lancet1, 60-61. 12Kalb, S.W. (1942): Effect of amphetamine tbenzedrine) sulphatepropadnne hydro- Chloride in combination with sodium delvinalon appetiteof obese patients./Med. Soc. New jersey39, 584-586. 13Scoville, B.S._ (1976):Reviewof amphetamine-like drugs by_the Food and Drug_Admini- stration. InConference on obesityin persopctive ed G.A. Bray, pp. 441443, Bethesda: Government Printing Office; DHEW NM 76-852.

1 42 138

14Silvennan,_11.I., Kreger,_B.E,, G.P., Karabelas, A.,_Paone_,_R. & Folcy, M._(1980j: Lack of sidc effects from orally administered_phenylptoanolamine and phenylpropano. 'amine with caffeine: a controlled three-phase study.Curr. Them Res. 28185-194. 15Silverstone, J.T., Turner, P. & Humperson, P.L. (1968): Direct measurement of the anorectic activity of die thylpropion (Tenuate Dospan). J.Can. Pharmaccd.8, 172-179. 16 US Pharmacopeial Convention (1981):United States Pharmacopeia Dispensing Informa- tion 1981.Rockville. 17Vemace, B.J. (1974): Controlled compositive investigation of mazinclnl, D-amphetamine and placebo.Obesity/liariatric Med. 3,124-129. 18Winick, C. (1982): Tolerance and abuse potential of phenylpropanolamine, unpublished report.

143 139 MS. OAKAR. Thank you, Dr: Conte: __Dr: SILVERMAN. Next is Dr. Marianne Sebok; internist; from Philadelphia, and associated with the Albert Einstein Hospital in that city. Dr. Sebok. STATEMENT OF DR. MARIANNE SEBOK Dr: SEBOK. Thank you: My- name is Dr: Marianne Sebok. I am a physician working in internal_ medicine_ I have been in the practice of medicine for 33 years and I am now in private practice in Phila- delphia, connected with the Albert Einstein Memorial Hospital, Frankford Hospital; and John F: Kennedy Hospital: I have a written testimony that I submitted to the committee. I would like to glire you, now, some highlights of this record. Obesity is a major health problem in the United States, affecting some 80 million _Americans; who are approximately 35 percent of the population. It can be a potential killer. Weight is usually a signficant predicter of cardiovascular disease in men and women, even when statistical adjustments are made for cigarette smoking, age; and hypertension. I have performed, as you can see here, double blind clinical studies on over 200 people who were in good health, to test the safety and efficacy of phenylpropanolamine; otherwise known as PPA. Patients who took phenylpropanolamine lost twice as much weight as those who were only on placebo. I have not observed, personally, any significant side effects from the use of PPA or phenylpropanolamine. In my opinion; phenylpropanolamine is safe and effective; if used as prescribed, not only as an appetite suppressant, but also as a nasal decongestant or cold medicine. And this was used, it was used as this for the last 50 years. Thank you. [The prepared statement of Dr. Sebok follows:]

PREPARED STATEMENT OF ARIANNE SEBOK, M.D., PHYSICIAN; AFFILIATED WITH J. F. KENNEDY MEMORIAL Ii SPITAL,-FRANKFORD HOSPITAL, AND ALBERT EINSTEIN ME- MORIAL CENTER, PHILADELPHIA, PA.

Good morning. My name is Dr. Marianne Sebok. I have been practicing-medicine for 33 yearsbeginning first in Hungary and then in Switzerland,In 1969, -1 came to the United States to begin a four-year residency at the Albert Einstein Medical Center in Philadelphia, specializing in haemotology and chemotherapy. In 1965, I was appointed staff physician at J. F. Kennedy Memorial Hospital in Philadelphia. I continued to practice there until 1973 when I left to start my own practice in Phila- delphia. Currently l -am affiliated with the J. F. Kennedy Memorial Hospital, Frank- ford Hospital and Albert Einstein Memorial Center -all in Philadelphia. My purpose in speaking to you today in twofold: First, to alert you to the stagger- ing mortality rates associated with obesity, and second, to point out the safety and effectiveness associated with phenylpropanolamineor PPAas an appetite suppressant to achieve weight loss. Phenylpropanolam;ne is a far Letter alternative in weight loss than crash diets, fads and liquid protein supplements. Phenylpropanolamine is a safe and effective appetite suppressant which can help overweight people lose weight. The only way to lose weight safely and effectively is to reduce the number of calories consumed. PPA can be used as an appetite suppressant while obese people learn new eating habits. When -I use the term obesity- I'm-referring to people -10 percent or more overweight. Government data puts that figure at 80 million Americansapproximately 35 percent of the total population. 144 140 Complicating diseasescoronary heart disease, cancer, diabetes, digestive diseases and cerebral vascular diseaseprofoundly increase the chance of early death when a person is obese. In a study by Lew and Garfinkel, a base of 750;000 men and women was used to calculate mortality rates as related to obesity, The recently completed Framingham Heart study also found a distinct relationship bitween overweight and mortality rates. Let me point out some highlights from these two studies. (Exhibit A) Weight is a significant predictor to total cardiovascular diseases in both men and women, even when statistical- adjustments are made for cigarette smoking,hypertension, age, left ventricular hypertrophy and serum levels of cholesterol and glucose. Weight is one of the best predictors of myocardial infarction, stroke and all type of cardiovascular death in women; ranking only behind age and blood pressure. Overweight females in their 50s, 60s and 70s are one and two-thirds more likely to die of cancer Digestive diseases are four times more likely to result in death in overweight men arid two times more likely in overweight women. Obese diabetic women in their forties are almost 25 times mor likely to die than if they were at normal weight. For both sexes, people are almost twice as likely to die of comp, 'g diseases if they are obese. Mortality resulting from complications of obesity is at its highest among people in their 40s and 50s. Obviously, for 35 percent of the American population, losing weight is a matter of life and death. Phenylpropanolamine is purchased by 10 million American each year for help in dieting. In my research with PPA as an appetite suppressant, I studied 134 overweight men and women in three separate double-blind trails: In the first, 54 patients were divided into two groups. One group received an appetite suppressant that contained 50 mg of phenylpropanolamine, and the other group received a placeb6 Patients were required to follow a 1,250 calorie nutritionally balanced diet consisting of high protein, low fat, and restricted amount of carbohy- drates. Patients took their test medication twice a day for six weeks. Background information on each patient was collected including physical condition; body weight frame, ideal weight percent overweight sitting blood pressure and pulse. At weeks two; four and six; the body weight, sitting blood pressure and pulse were rechecked. Patients were also questioned about adverse reaction. After six weeks of evaluation, there was a statistically significant weight loss in the medicated group as compared to the placebb at a .05 level of confidence. The second study involved 72 obese adults. The study procedure was identical to the first study, except that patients were not restricted to a 1,250 calorie diet. Fifty-six patients completed the study. The PPA group lost a significant amount of weight as compared to the placebo group at a .01 level of confidence. Most important however; is that throughout the study no clinically significant variations in sitting blood pressure or pulse were observed. In the final study, 70 patients were selected and 49 completed the study. The only side effects reported were minor, subjective symptoms that appeared in both the medicated and the placebo groups. These occurred among some people in both groups and were considered mild and did not persist. This six-week evaluation revealed that of those patients taking Prolamine (35 mg phenylpropanolamine phis 140 mg caffeine B.I.D.) over a six-week period, 35 percent lost eight pounds or more and 22 percent lc t six pounds or more Of those taking a placebo, only nine percent lost eight pounds or more and 22 percent lost six pounds or more Of those taking phenylpropanolamine, 35 percentlost five percent or more of their initial body weight, while only four percent of the patients on placebo lost 5 percent of their initial body weight, No significant changes in either blood pressure or pulse measurements were indicated during the test peri6ds in comparison with the baseline me-asurement. 141

Sebek, M., Exhibit

A. influence of Obesity on Mortality Rates of Men and Womenin Disease and Non Disease States

INFLUENCE OF OBESITY ON MORTALITY RATES OP MEN AND WOMEN

IN VARIOUS DISEASE AND NON DISEASE STATES

MORTALITY RATIOS FROM CORONARY HEART DISEASE BY AGE AND SEX IN RELATIONSHIPTO DEATH RATES OF THOSE 90-1000 OP AVERAGE WEIGHT

WEIGHT INDEX

AGE GROUP SEX 4080 080-089 090-109 110-119 120-129 130-139 140+

30-39 M 0.54 0.79 1.00 I;46_ 2.03- 1.49 NOD 7 NOD- 0.88 1.00 2.27* 2.29* NSD NSD_ 40-49 M 0.60 0.74 1.00 1.34 1.67 1.93 1.98 F 1.00 0.65 1.00 1.59 2.71 2.71 3.61 50-59 M 0.77 0.86 1.00 1.28 1.41 1.76 2.16 F 0.98 0.82 1,00 1.45 1.54 2.:6 3.1: 60-69 M 0.90 0.94 1.00 1.21 1;22 1.34 2.18 F 0;93 0.89 1.00 1.30 1.43 1.65 1.88 70-79 M 1.17 1.02 1.00 1;09 1.22 1.52 1.41 F 1.06 0.97 1.00 1.09 1.25 1;29_ 1.41- 80-89 M 1,32 1;00 1.00 1.12 0.81 0.61* 1.43* F 1.11 1.04 1.00 0;97 0.92 0.61 1.23

NSD._aot_sufficient data (less than 5 observed deaths). *Mortality ratio based on only 5-9 observed deaths.

Coronary heart disease was particularly high among women in their -forties and fifties; /n_the_veight_index_category 140 plus female mortality from thiscause was from three to three and a half times higher than that in the 90-109 weightindex-category. Among men in the same age range corresponding coronary disease mortalitywas only About two times_ higher. At ages under 70 coronary disease mortality appears to besomewhat lover among underweights than among those of about average weight in both sexes.

27-436 0 - 84 - 10 142

RELATION TO DEATH RATES OF ALL SITES_RY_AGE AND SEX IN MORTALITY RATIOS FROM CANCER OF THOSE 90-1092 OF AVERAGEWEIGHT

Weight Index 120=12,9- 130-09 10+ OB0-089 -----090-409 110-119 Age Group-----Sex <080 NSD NSD 1;00 0.90 kaL 1.93* 1.36 0.92* 1.16 30 -39 M 1.00 1.47 0.93 0.85 0;84 1.10 1.19 1.31 . F 2.96 1.21 1.00 1.19 1.37 40-49 k 1:49 0.97 1.14 0.94 1:00 1.09 1:52 F 0t95 1.08 1,13 1.46 1:13 1.00 1.12 1.67 50-59 11 1.14 1.16 0.92 1.00 1.17 1.13 F 1.00 1.00 1;05 1.12 1.00 1.29 1.79 60-69 H 1.16 1.16 1.37 0.97 1.00 1:32 1.15 F 1.11 0.95 1.09 1.00 1.59 H 1.25 1.09 1;01 1.32 70-79 1.00 0.99 0.72 0.3i 1.11 NO- NO F 1.00 0;66 1.19 0.79 1.35 1.98 NSD B0 -B9 H 1:00 1.22 F 0.80 0.99

fiiiIe_overweights vas evident only from Cancer among speci- Significantly higher_Sior:alitY sixties and seventies_of_agef 140 plus, in_thi_fifties, the.averaffe_Weight index categovi in the weight_index categorytwo-thirds_higher than that In fiCilly it was about one and among male overweight* wasless pronounced than_among_ Excess mortality from cancer weight index category 90-109. third to one half higher in the women-ovirweights: being only about one 140-plus.

14i 143

MORTALITY RATIO FROM DIABETES BY ACE AND SEX IN RELATION TO DEATH RATES OF THOSE 90-109° OF AVERAGE WEIGHT

Weight Index Age Group Sex (080 080-089 090-109 110-119 120-129 130-139 140+

30-39 RI NO NSD 1.00* NSD NSD NSD NSD F NSD NSD_ NSII NSD NSD__ NSD NSD 40-49 M NSD 1.99 1.00 2.64 3.56* NSD NSD * NSD NSD- 1.00 3.55 9.56 NSD 24.59 50-59 M 1.17.1. 0.90 1.00 1.71 2.88 5.35 7.06* F 1.00* 0.64 1.00 2.28 4.35 7.12 12.32 60-69 M 0.71* 0.64 1.00 1.33 2.87 2.07* NSD F 0.60* 0.66 1.00 2.05 3.54 338 4.12 70-79 M NOD- 0.69 1.00 1.52 1.74 NSD NSD r 0.55* 0.64 1.00 1.51 1.65 1.75* 4.40* 60-89 M NSD NSD 1.00 2.79_ NOD NOD NSD F NOD NSD 1,00 1.02* 2.90 NSD NSD

NSD. Not sufficient data (less-than 5 observed des ths). *Mortality ratio based on only 5-9 observed deaths.

Mortality from diabetes was-reltively highest among women overweights in their forties and_fifties;_the_excess_sortaIity_from diabetes_diminished_with_advancing sge among overweight women. Among men overveights at ages under 70 the excess mortality was distinctly lower than among women and-did not vary as much -by -age.- Note that the mortality ratio of a female in her forties at least 407 overweight is 24.59! 144

AND SEX IN RELATION TO DEATH OF THOSE MO4TALITT RATIOS FROM DIGESTIVE DISEASES BY AOE 90-109% OF AVED!GE WEIGHT

Weight Index 110-119 120-129 130-139 140+ Ago Group Sex (080 080-089 090-109

lip NO 1.77* 1.00 NSO NO 30-39 H NSD NSD 1.00 NSD NO NSD F NSD 1.58 1.00 1.67 2.76 6.60 NO 40-49 M 0.91* 1.35 1.27 NSD__ NSD 3.61 F 2.07 0.98 1.00 1.20 2.10 3.23 5.11 1.51 1.36 1.00 50-59 M 2.13 2.15* NSD F 1.71 1.13 1.00 1.98 1.65 1.45_ 1.80* 4.67* 60-69 H 1.65 1.09 1.00 1.61 0.98* 1.86* NSD F 1.75- 0.56 1;00 1.52 1.14* NSD NSD 70-79 H 1.26* 1.22 1.00 1;88 2.54 3.77 NSD F 0.96 0.64 1.00 1.55* NSD NSD NSD 80-89 M NSD NSD.._ 1.00 1.08* NSD NSD NSD F NO 0.98* 1.00

HID Not ifficient data (less than 5 observed deaths). *Mortality ratio based on only 5-9 observeddeaths.

6venmights of both sexes 4as_from_digestivo_ The second highest_reIative_o4rta1ity among the_mortaIit),_from these diseases was four In the 140 plus weight index category diSiaSeS. foi males_and two and a quarter times for females._Ent:. times that in the 90-109 weight index weight index category- recorded distinctly higher male and femile iinderVetibta_inthebelov 80 death rates. approximately one and a half timesthose in the 90-109 weight index. 145

SUIOIARY

---- MORTALITY RADIOS FOR ALL ACES COMBINED-IN-RELATION TO THE DEATH RATE OF THOSE 90-1091 OF AVERAGE WEIGHT

Weight Index 7th Rev* /CD Sex 080 080-089090-109 110-119 120-129 130-139 140+

Total deaths H 1.25 1.05 1:00 1.15 1.27 1.46 1.87 -- F 1.19 0.96 1.00 1.17 1.29 1;46 1.89 Coronary_heart 420 H 0.880.90 1.00 1.23 1.32 1.55 1.95 disease-- F 1.01 0.89 1.00' 1.23 1.39 1.54 2.Q7 Cancer; aII sites 140-205 H 1.33 1.13 1.00 1.02 1.09 1.14 1.33 F 0.96 0.92 1.00 1.10 1.19 1.23 1.55 Diabetes 260 H 0.88 0.84 1.00 1;65 2.36 3.51 5.19 - F 0.63 0.61 1.00 1.92 3.34 3.78 7.90 Digestive 540-542 m 1;39 1.28 1.00 1.45 1.88 2.89 3.99 disease 570-578 - __ __ 584-586 F 1.580.92 1.00 1.66 1.61 7.19 2;29 Cerebral vascular 330-334 H 1.21 1.09 1.00 1.15 1.17 1.54 2.27 disease F 1.33 0.98 1.00 1.09 1.16 1.40 1.52

International Classification of Diseases, 7th Revision

Ibe_mortality experienced in each weight index category from allcauses of death and_from each of five broadcause_of_death_classes_is shown above forall-ages-combined by am. These causes were-shown because they are the major causes of-deathor have been shove in-otherstudi. tobe- associated with overweight. -By definition the mortalityratios in the 90-109 weight ind, category are all 1002. It should_be_neted_that_the_mortality ratios shown for otherweight index categories have all been adjusted for time period andsmoking Claii. For males the optimal mortalitt,weight_indei_wit_90,1094-for-females those with weight indix_80,89_recorded death-rates 41 lower than those in the 90-109widths indei Category._ In both sexes relative- mortality- vas higher among those in the below 80weight index category than in-the 90-109-weight index. With increase in weight_the_mortality_ratio among males roseto 115Z_for_thi_110,119 weight-index category. 127% for the 120-129 weight indexi 146% for the 130-139 weight index and 187%_for_thi_140 plus_weight index.- _ The corresponding mortality ratir among women were 117, 129, 146 and 1895 respectively. Data for age groups are presented on the next page. 146

SEX IN RELATION TO DEATH RATES OF MORTALITY RATIOS FROM ALL CAUSES-OF-DEATH BY AGE AND THOSE 90-1095 OF AVERAGE WEIGHT

Weight_Index 110-119 120-129 130-139 140+ Age Group Sex 080 080-089 090-109

1.37 1.77 1.20 1.71 30-39 M 1.32 106 1.00 1;27 1.61 F 1.24 0.95 1.00 1.33 1.49 1;24 1.63 1.81 2.19 40-49 M 1.09 1.01 1.00 1.51 2.02 F 1.20 0;94 1.00 1.09 1.38 1.18 134 1.51 2.02 50-59 M 1.24 1.02 1.00 1.46 1.62 2.31 F 1.19 0.92 1.00 1.29 1.23 1.38 1.65 60-69 M 1;24 1.06 1.00 1.12 1.59 1.85 F 1.19 0.96 1.00 1,27 I.37 1.06 1.08 1.30 1.41 70-79 M 1.32 1.12 1.00 1.00 1,08 1.15 1.34 1;65 -- F 1;20 0.97 1.11 1;04 0.83 1.53 80-89 M 1.40 1.05 1.00 0.99 1.04 1.10 F 1.21 1.07 1.00 0.95

*Mortality ratio based on only 5-9 observed deaths.

overWeightsvai highest_in_the For ill_Causes of death combined, the excess mortality -among The excess (utiles and fifties fur both sexes-and-tended_todiminish with advance in age. mortality of underweights (below 809eight indexcategory) was generally aomewhat higher anon: underweighte Wei Uniformly about 207- Min than among women; the excess mortality among female

REFERENCES-

Vatiatione_in Mortality by Weight Among 750,000 1. Lew, E.A., and L. GarfittRiIi Men and Wien; Journal of Chronic Diseases. 32: 563-576, 1979.

Society of AttUaties. Chicago, 1959. 2. Build and Blood Pressure Study 1959. _ _ The FrSmingham 3. Gordon, T._ind W.B. Kennel: °basic and-Cardiovaseular-Disease. , 6. Study. Clinical Endocrinology and Metabo San. -

151 147

Ms. DAKAR.Thank you very much, Doctor. Dr.SILVERMAN.Thank -you; Dr. Sebok. My next colleague is Frank Funderburk from the Johns Hopkins University, who will present the highlights of his study. Ms.OAKAR.Well, this is an interesting study because you probably have heard your colleagues talk about it Dr.FUNDERBURK.Yes. Ms.OAKAR.Too bad you couldn't have gone first. STATEMENT OF DR. FRANK FUNDERBURK Dr.FUNDERBURK.In the minute that I've been allotted I don't think that _I can adequately respond to the questions that have been raised. Ms.OAKAR.Please feel free to respond. Dr.SILVERMAN.Thank you. Dr.FUNDERBURK. Iwould be happy to submit to the committee additional information on this study and ask that that be entered into the record along with the written testimony that I've submitted _today. Ms,OAKAR.In fairness to you, if you do want to respond to the specific points that they made, please feel free to do so. It's fine. Dr.FUNDERBURK.Thank you My name is Frank Funderburk and my scientific training is in experimental design and statistics. I'm part of a research team at the Johns Hopkins Medical School, which is under the direction of Dr. Ira Liebson. Our group has conducted a_series of studies on the effect of phenylpropanolamine in doses of75milligrams. This is the dosage that is currently marked in over-the-counter diet aids. Phenylpropanolamine is also used widely in cough/cold preparations which are widely used. Our studies at Hopkins were carefully controlled investigations in which more than 200 subjects were intensively studied over a 12- hour period. In our studies we found no overall clinically significant change in blood pressure, or pulse as a result of phenylpropanolamine. The sweets in the studies did not experience emotional highs or lows, as measured by standardized mood assessment and inventory techniques, and these emotional highs and lows are the effects that you would normally expect to find in drugs of abuse. In response to the presentations that have been wade earlier by Dr. Young and Dr. Mueller, we have done some analysis of the data on individual cases. And additional study is still going on with that. But we found increases in blood pressure in both placebo groups and subjects treated with phenylpropanoiamine of large magnitude. We currently attribute those to a circadian variation and not to the effect of phenylpropanolamine. And as I say, I will be submitting additional information to the committee detailing those results. [The following statement was subsequently received from Dr. Funderburk:]

152 148

SUPPLEMENTAL TESTIMONY SUBMITTED BY FRANK R. FUNDERBURK In her recent Congressional Testimony, Bambi Batts Young of the Center of Sci ence and Public Interest criticized the analyses and interpretation of studies of phenylpropanolamine (PPA) conducted at lkhavioral Pharmacology Unit of The Johns Hopkins University School of Medicine. Since her statements are a matter of public record, we feel that it is important to point out the deficiencies in her analysis. Therefore, in this suppLemental testimony, we will provide further details on the data from our studies; focusing on the points raised by Young's testimony.

OVERVIEW OF THE RESEARCH The studies under discussion compared the effects of 75mg doses of PPA (in two dose forms) with those of matching placebo in carefully controlled clinical investigations tfor details, see(1)1. In one study ("parallel groups design"), 150 participants received either a 75mg sustained release PPA product, a 25mg immediate release PPA product at four hour intervals (for a daily total of-75mg) or a placebo (inactive product of "dummy pill"). Participants were studied for a 12 hour perindfolowing initial drug administration. The protocol called for measures of blood pressure fir three body positions), pulse, and subjective state throughout the session. In the second study ("cross-over-design"), 59 participants were tested, using a similar testing protocol, under both placebo and active drug conditions (75mg sustained release PRA). Data from both studies were analyzed using a statistical procedure (analysis of variance) which measured the effects of drug treatment (i.e., active drug versus placeba), time of measurement fi.e., time post-medication), and the interaction of these factors (i.e., did the drug treatments show statistically different effects over the course of the session). Further details on the statistical analysis is presented in our written testimony of July 21, 1983.

SUMMARY OF RESULTS In the first stutir (of 150 cases), we found no statistically significant blood pressure differences between the groups receiving PRA and the one which received placebo. Normal fluctuations of blond pressure over the course -of the day were found in both the active medications and placebo groups. No evidence of adverse subjective effects attributable to active drug treatment was noted. In the Second (cross-over) study, a statistically reliable difference between placebo and active PPA treatment was reported on several of the blood pressure variables indicating that the average blood pressure difference between the PPA and placebo was generally greater than zero. The actual differences ranged from .83mm Hg tstanding systolic) to 3.37mm Hg (supine diastolic) with an average difference of less than 2mm Hg Such small_ differences_although statistically reliable, were not regarded as clinically significant. No evidence of adverse subjective effects attributable to active drug treatment was noted.

SUMMARY OF YOUNG'S CRITIQUE In her testimony, Bambi Batts Young argued that data from these studies were misinterpreted by the investigators. She claimed that here analysis indicated that the results of the -Ho pkins Study were consistent with those of Horowitz (1980) and indicated "alarming blood pressure :names& associated with PPA. Her argument centered on three major issues. She maintained that; (1) Differences in time course of drug effects were ignored in the analrsis (e.g., "unaccountably, after taking that whole sequence of measurements*_the team lumped all readings from the PPA day into one average, and all the readings from the dummy-pill in another average, and noted that there was little difference between the two."). (2) The group design and associated analysis precludes and/or obscures an analysis of individual responses to PPA (e.g.,if the average goes up ... you can bet that the values for_someindividuals go a whole lot higher (3) Individual case reports provide some evidence of adverse PPA efficts on blood pressure (e.g.; "And if you look at the individual figures, that is exactly what you find."). An objective evaluation of the analysis presented in support oilier argument, however, indicates a misunderstanding of the basic scientific and statistical princi, ples which were involved in our clinical evaluation of PPA effects. Iii the following section, we will briefly consider the basic scientific logic- underlying clinical investigation of drug effects. Next we will iiscuss the results of the Hopkins Study considering each of Young's major points in some detail. Finally, we will summarize our

15,i 149

conclusions in light of our- original investigations, Young's arguments,our review of the evidence, and other relevant clinical data

A BRIEF OVERVIEW OF CLINICAL RESEARCH The purpose of conducting clinical drug evaluations is to better urderstand the nature of the effects of a drug. Although no single studyno matter how well con- trolledcan provide conclusive evidence of the presence or absence ofa particular drug effect, clinical evaluations are designed to provide the best possible evidence possible in a particular research context. Well-controlled clinical trials followa well- defined set of rules for describing and explaining the events which theyare designed to study. These rules include empirical verification ("what didyou see), operational definition ("what were_ the criteria"), controlled observation ("when/how did you see this"), statistical-verification ("haw likely is this result") and empirical confirmation ("who else has found similar results The scientific value of any clinical evaluation depends on the extent to which the analysis follows these basic scientific rules. The well-controlled clinical trial will specify: (1) The types of measures to be taken (empirical verification). (2) The criteria for measuring responses of interest (operational definition). (3) The circumstances under which measures will be taken, control for extraneous variables by various techniques, including random assignment to treatment (controlled observation). (4i The type of statistical analysis to be used (statistical verification). (5) The relationship of results/analysis to existing research (empirical confirmation). Such rules allow researchers to make valid observations which eliminateor control (to the extent possible) extraneous variables which could influence the outcome of an experiment. In addition, adherence to these rules insures that the results ofa particular study can be interpreted statistically (e.g.; in terms of probability statements reg_ardin_g a particular outcome). In this regard; it is important to note that in order to determine if a relationship exists; the information in both experimental and control conditions must be taken into account. (It is a very common mistake to draw conclusions based on relationships which appear in one condition withoutcon- sidering the other). Even then, however, the interpretation of the result of a particular study must be made with consideration to other relevant research findings. Let us now turn our attention to the "Hopkins Study".

A RESPONSE TO YOUNG'S CRITIQUE OF THE "HOPKINS STUDY" The "Hopkins Study" was designed and conducted according to sound scientific methods. Data were analyzed using well established scientific a-nd statistical procedures. The conclusions drawn from the studies were quite consistent with a large body of independent clinical research on PPA. The overall conclusion from this investigative effort was that PPA in acute daily doses of 75mg did not have clinically significant adverse effects on blood pressure, pulse or mood. Young maintained that our analyses overlooked a number of important factors, including time course of drug effects, limitations of group designs and consideration of individual differences. As a result, she argues the conclusions drawn from this research are inappropriate. Let us consider each of her major points: 1. Wore time course effects considered? Yes. Young implied that the effects of the various drug treatments over_time were ob- scured by presenting only "average" scores on the variables studied. This is simply not the case. The analysis of variance model used to analyze the data asked the following questions of the data: (1) Were there any overall differences between drug treatments? (Main effect for drug treatment). (2) Were there any trends/changes over the course of the session? (Main effect for measurement occasion). (3) Did the various drug treatments have different effects at different times during the session (drug x- measurement occasion interaction)? As in most types of statistical analysis, these questions are answered in terms of the probability of finding differences between the various measures which are greater than those which would be expected by chance. Thus, even though one group may have a different average than another, either overall or at one point in time the relevant question is whether this difference is greater than one would expect based on a random sampling from the population studied. 150

In our first study (II= 150; parallel groupsdesign); our analysis did not indicate any statistically reliable differences_in blood presSure between thevarious drug treatments either overall or at the various measurementoccasions, although (as expected) general fluctuations in blood pressure wereobserved over the course of the In our second study (n=59; cross- session for participants in all treatment groups. drug over design), we found a small,but statistically reliable, difference between 2 mm Hg) on most measures of blood gressure treatments (averaging approximatelyvariation, these differences were constant over the In general, apart from random showed course of the session: Subjectsin both active drug and placebo conditions normal fluctuations over the course of the session. 2, Did thegroup design obscure importantfindings? No Young argues that group designs such as ours;obscure atypical responses ("out- While such an occurrence is possi- liers", in statistical jargon) in a treatment group. conduct- ble, a well-conducted analysis examinesfor such potential problems. Before ing_our formal statistical analyses; weexamined our data in terms of both change from baseline (pre-SeSSion) and absolutepeak effect Some subjects did, indeed, show quite striking increases in blood pressure at somepoint in the session. However, as noted in our oral testimony on 21 July 83,such fluctuations occurred in both_place- bo and active drug treatment groups.Since these effects appeared to be random oef currences, independent of drugtreatment_condition, it was considered appropriate to include such scores in our overallanalysis for all treatment groupS. For example, in the_parallel groupi design, a subjectin the placebo condition showed a supine occasion; while a similar reading blood pressure of 176/116 on one measurement75ing sustained release group, and also (164/116)_was observed in one subject in the than in one 25mg Lid. group (154/110).Peak blood pressure readings of greater 94mm Hg were found with approximately_equalfrequency in all three drug treatment groups in the parallel groupsdesign, and this is shown in Table 1.Similar results were found in the cross - overdesign; as shown in Table 2. 3. Do individual ease reports provideevidence of adverse PPA effects? No. As noted above, many subjects treatedwith placebo showed dramatic blood pres- of _the session. In her testimony;Young showed sure increases during the courseincreased dramatically on the daythey received cases in Which blood pressure increases are -also seen under placebo treat- active medication. Similar "dramatic" associated with interpreting an individ- ment,Figure 1 and 2 illudtrate the problems experimental session. Using Young's ual's fluctuations in blood pressure over a long in -Criterion, one would suspect that the'passing attack of serious hypertension" these two subjects was the result of placebo(no drug). As noted above, thefrequency over-94mm Hg was evenly distributed amongthe of peak blobd pressure readings of peak_response (using analysis ofvariance various treatment groups_An analysisbetween baseline blood pressure andpeak procedures) applied to difference scores design, blood pressure also confirms this finding(see Table 3). In the parallel groups differences between peak blood pressurereadings were no statistically significant supine found -in any of the three body positions.In the cross-over design, only the statistically reliable (mean difference --.5,8mmHg diaitolic difference measure was presented in our at peak). Theie findings areentirely consistent with the results report,: to FDA and in our writtentestimony submitted on 21 July 83.

SUMMARY The data reviewed in this supplementaltestimony support our original_ conchk doses of 75mg. Our analyses suggestthat sions regarding the effects of PPA in dailysignificant increases in blood pressure even this dose does not produce clincially examined. In our parallel_groupsdesign; when peak blood pressure effects were observed slightly more "hypertensive" supinediastolic blood pressure readings were (10 percent) as compared withPPA (6 percent). in the subjects treate&_with placebb "hyperten- In the cross-over design, pattern was reversed; with slightly more sive" Supine diastolic readings in subjectstreated with PPA (11.8 percent) as com- of these differenceS is statisticallyreliable. pared with placebe (5 percent). Neither peak meas- Even smaller differences betweenactive drug Arid placebo were found in ures tak_en whilesubjects_were sitting or standing Young's analysis of the results of ourstudy failed to consider a numberof impor- did not consider the results of ourparallel groups tant factors. in particular; Young frequently associated_ with "hyperten- Study in which placebo treatment was more possibility sive episodes ", Nor d.:1 her analysisgive adequate consideration to the that many of the "hypertensiveepisodes!' in both placebb and drug treatment groups could be attributed tonormal circadian variation in blood pressure: J55 151

lleruse of individual cases to illustrate "adverse" effects of PPA is particularly inappropriate since both routine statistical analyses and analysesof peak effects indicated very little systematic difference in bloodpressure response between treatment groups in either the parallelgroups designor in the cross-over desivi "7:e statistic-ally reliable finding of small PPA-associated effectson supine diastolic n,d pressure iS consistent with our previous report._ In the present study; themean difference between treatments was 5.8mm Hg, while theaverage difference between treatments (over the session) was 3.37mm Hg;- for supine diastolic blocklpressure. Our_ results are consistent with an extensive body of clinical literaturesuggesting that_PPA, in the dose examined in our study, does not have adverse clinicaleffects on blood pressure, pulse, or mood.

TABLE 1.-PARALLEL GROUPS DESIGN-FREQUENCY OF PEAK OF DIASTOLICBLOOD PRESSURES >94

Standing _ &upine Condition

Yet Nd Yes No Yes No

PPA 75(S R ) 1 49 3 47 3 47 PPA 25 )10 50 1 49 4 46 Placebo 50 3 47 5 45

TABLE 2.- CROSS -OVER DESIGN-FREQUENCY OF PEAK DIASTOLIC BLOOD PRESSURE >94

Standing Sitting S6pae Condition

Yo Nd Pet No Yes No

PR 75(S R.) 2 57 4 55 7 53 Placebo 59 59 3 56

TABLE 3(A). -PEAK INCREASE (FROM BASELINE) IN DIASTOLIC BLOOD PRESSURE-PARALLEL GROUPS DESIGN

Candition Standing Sitting Supine

PPA 75 5.40 9.32 14.08 PPA 25 (Id 8.58 7.32 11.12 Placebo 8.12 6.46 11.00

TABLE 3(B). -PEAK INCREASE (FROM BASELINE) IN DIASTOLIC BLOOD PRESSURE=CROSS-OVER DESIGN

Condition sutoing &Ring Supine

PPA 75 (S.R.) 11.39 7:27 15:39 Placebo 7:98 8.40 9.59 'p< 01

REFERENCES 1. Funderburk; F.R. Testimony before the -House Select Committee on Aging, Sub- committee on Health and -Long Term Care. July 21, 1983. 2. Horowitz, J.D. et al. Hypertensive response induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1980, Jan. 12, 60-61:

151; 74)

143 0 0 9.

KEDIK.Arno4 PO= I Wuts 12; S 153 Dr. FUNDERBURK. Thank you. [The prepared statement of Dr. Funderburk follows:]

PREPARED STATEMENT O1 FRANK FUNDERBURK, M.S.; THE BEHAVIORAL PHARMCEUTI- CAI. RESEARCH UNIT OF THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE Good morning. My name is Frank Funderburk. I have a Master's degree in biostatistics and am a collaborating investigator associated with the Behavioral Pharma- cology Research Unit of the Johns Hopkins University School of Medicine in Balti= more Maryland. I was part of the team, led by Dr. Ira LiebSon, Which conducted a number of studies of PPA. I would like to summarize the results ofour research to you. The focus of the research we have been doing on phenylpropanolarnine has been studying its effects on mood alterations Brat I am well aware that many of the crit; ics of phenylpropanolamine state that the drug acts like amphetamineor "speed"; that it produces a euphoric "high" in users. In our studies we measured mood alterations using both subjective methods; where the suWect is asked by the researcher how he feels; and, using objective methods, notably two scientifically accepted test scales that were designed Skcifical: ly to measure alterations in mood states: the Addiction Research Center Inventory, and the- Profile of Mood States. In neither of these analyses did PPA show amphetamine-like effects. PPAwas _not rdated to either euphoria or sedation. In fact; in one of the only statistically findings in three studies of PPA, there was some evidence to suggest that if PPA pro= dewed any alterations in mood at all, it was to reduce the fatigue and boredom associated with a 12-hour experimental session in a relatively unstimulating laboratory environment. _This is not to say that no mood changes were observed over the course of a 12- hour experimental period. For_ example, most subjects had more energy in the Morn= ing than they did at the end of the day. They were all pretty bored by the end of the dayas one might expect. But, with the one exception I mentioned, these changes in how the subjects felt were identical in both tests and control groups. Now, as for the effect cf phenyipropanolamine on blood pressure: In one study we carried out on 150 subjects, we found -no change in blood pressure that could be tributed to taking a 75 mg dose of PPA. Ye% there were changes over the 12-hour course of the study; and yes,- there were &ifferences in when these changes occurred between the test_and control groups. But none of these differences reached statisti. cal significance; all of them were within the range of what a medical observer would expect to see over the course of a day in &normal, healthy individual. In another study of 59 Individual% we did observe some small differences in blood pressure between the subjects taking a 75 mg dose of PPA as compared to those takings placebo. Asa research scientist, I view these differences as statistically sig- nifiL,Irt. and have reported them as such: But n a physician; Dr. Liebsori did not regard the.-e differences =as clinically significant. The- average overall difference in blood pressure between the two groups was less than 2 mm of mercurythat means blood pressure of say 120 over 80 as com_pared to 122 over 82. Our test methods involved giving 75 mg of phenyipropanamine to subjects either as one time-released dosages; or as three separate dosages of 25 mg each at four- hour intervals. In one test using 150 subjects, reactions were compared to a control group receiving a placebo on the same dosage schedule. In another test of 59 subject% the participants served as their own controls;_they took PPA on the test day, and, a week_later, took a placebo; on the same dosing schedule. Roth tests were carried out over a 12-hour period. Blood pressure; pulse and mood-alteration measurements were taken nine times: before any drugs were given, one half-hour after drugs were given, and then at hourly intervals. Doe§ PPA pr6duce a "high"? No Does taking it result in an amphetamine-like euphoria?_No. Is it "speed"?NoIn our scientifically controlled studies of 75 mg PPA we found none of the euphoric, sedative; or amphetamine-like effect normally associated with drugs of abuse. Further; sw; found no clinically significant changes in-blood pressure, pulse or mood. I am submitting my comments, and copies of the studies I referred to to be entered into the record. Thank you. 154

EFFECTS OF PHENYLPROPANOLAMINE ON BLOOD PRESSURE;

PULSE; AND MOOD:

PARaLEL GROUPS DESIGN

Study Site Behavioral-Pharmacology Research Unit_ Johns Hopkins University Uhool Of Medicine Baltimore City Hospitals 0-5-West 4940 Eastern Avenue Baltimore, Maryland 21224

Contact: Frank R. Funderburk- Director, Clinical Consulting. ANTECH4-InC.__ (301) 997=0880

Date: October 8, 1982

159 155

TABLE OF CONTENTS

ABSTRACT

INTRODUCTION 2

OBJECTIVE

RATIONALE 3

INVESTIGATIVE METHODS 3

Siddects 3

Design and Procedure 4

1. General Procedures

a. Subject control 4

b. Meals and focd restrictions 5 c. Drug administration

d. Clinical measurements 6 2. Design

RESULTS

DISCUSSION

REFERENCES 10

APPENDIX 1:

FIGURES 35 156

FINAL REPORT OF

CLINICAL PROTOCOL NO. 82 -8(Ai

An E;aluation of the Acute Effects of Phenylpropanolamine in Normal Volunteers: Parallel Groups Design

Sponsor: ThOmpson_Nedical Companr; Inc. 919 Third Avenue_ New YOrk; NY 10022

Investigators: Ira Liebson Qorge Bigelow Roland_Griffiths Frank Funderburk

Protocol develdped by: The Clinical Consulting Group ANTECK_Inc. and the Behavioral Pharmacology Research Unit

Contact: Frank Funderburk (301) 997-0880

Project start date: 25 -June 82

Project completion date:111-August 82 157

ABSTRACT

One hundred fifty (150) healthy normotensive volunteers (mean age 25.9)

participated ina double-blind, placebo controlled comparison of the effects

of phenylpropanolamine HCL on blood pressure, pulse; and mood. Two dosage

forms of phenylpropanolamine were studied (75 mg sustained release and 25 mg

t.i.d.) in comparison with placebo. Subjects were randomly assigned to one of

the three drug treatment conditions. Subjects in one group (Group A) received

the 15 mg sustained release dose on their first medication occasion and

placebo capsules on the other two dosing occasions; Subjects in another group

received 25 mg capsules at each medication occasion (Group 8). Subjects in

theother group (Group C) receivedplacebo at each medicationOCCASidr.;

Subjects were studied for a 12 hour testing session.

Measurements of blood pressure (sitting,standing, and supine), pulse; and subjective drug effect ("mood") were obtained 9 times during the session at baseline (prior to drug administration) and at 1/2 hr; 1hr; 2 hr; 4 hr, 6

hr, 8 hr, 10 hr, and 12 hr post initial dosing.

Mixed design analysis of variance revealedno main effectsfor drug

treatment on any ox the measures. As expected, all measures showed main effects for time of day (circadian effects); indicating that subjects' physic- logizal and subjective state changed over the course of the session. These changes were not, hower, related to the drug treatment condition.

162 27-436 0 - 84 - 11 158

RATVAALE

PPA has be'n used as in anorexiant for over 30 years andhas long been an ingredicnt In many over-the-counter cough-cold produCts(see; e.g.; Silverman,

PPA... 1980); Recently; however, some reports have appeareJ suggesting that generally in doses higher than those approved for over- the -Counter use in the

United States--may be associated with adverse hypertentiVeeffects or other

Oiet2,1981). amphetamine -likeside effects (e.g.,Horowitz, 1980;

Silverman et al.(1960) reported no adverse hypertensive effectt Of a 25 mg

OOSe Of PPA either alone or in combinationwith 100 mg of caffeire. Hoebol

(paper in preparation. 1982) noted no adversehypertensive effects of 150 mg

PPA (75 mg b.i.d.) in a group of sixnonmotensive individuals;

The present study was undertaken to extend theexamination of PPA effects

on tilded pressure; pulse, and subjectivestate in a larg2, carefully

controlled Clinical investigation.

IMESTIGATIK METHODS

Subjects

Subjects were 150 healthy normalvolunteers (mean age 25.9) (both male 63 blacks. 3 and female). The study population consisted of 83 caucasians.

orientals. and 1 American Indian.Approximately 581 of the subjects were men; infJecieill consent ono nod been screened to meet thefollowing All had given

criteria:

6 159

a. between 18 and 55 years of age

b. no current use of medications which would compromise the

validity of the evaluation of the test products

no physical contraindications to consumption of PPA at

the dose levels used in this study

d. no history of severe emotional disturbance; chronic alcoholism;

or drug abuse

e. evidence that the subject would participate in the. research and

be cooperative

f. good general health based on a medical history interviei,

conducted within one month of the study start anda recent physical examination

female subjects certified that they were not pregnant or nursinc

a baby for the duration of the study.

iles-i-onandP-rece-dure

Subjects were randomly assigned to one of three treatment groups upon

entry into the study. The basic investigative procedures followed for each

subject are detailed below.

1. -General Procedures

a. Subject control. Subjects were instructed to be free of all medications for the week prior to the first administration of a test produM

Subjects who had ingested substances which could have compromised the validity ofthe study were excluded. Study medicationswere administered under clinical supervision. Subjects remained at the test facility for the entire testing period (approximately 13 hours) on the test day;

164 160

b. Meals and food restrictions. On test days subjects were provided with a choice of standard noontime meals. Foods containing xanthines

(e.g., coffee, tea, cola) were not permitted On study days.

C. Drug administration. In this investigation two currently

Marketed dose's of test products containing PPA (PPA, 25 mg,t.i.d. and 75 mg

Sustained release PPA) were being compared with placebo. On each test day subjects received three administrations of a test product. Study medications were identiCalin appearance and were labeled in code so that neither the investigator nor the subject could know which medication wasbeing

8:00 administered. Doses were given at 4 hour intervals (e.g., approximately am, 12 noon, and 4:00 pm). Subjects were randomly assigned to one of three treatmentcondi-

received the 75 m4 sustained tibilS. One group of subjects (Condition A) placebocapsules on releaseproduct attheirfirst dosing and matching 25 tag subsetpient deting5. Another group of subjects (Conditio B) received

PPA at each of the three dosirgs; Finally, one group (Condition C) received placebo at all three doiTogs; This dosing schedule is illustrated in Table 1.

Table 1

Dosing Schedule on a Test Day

Dose 1 Dose 2 Dose 3

fapprox. 8:00 an) (approx. 12 noon) (approx. 4:00 cm)

placebo Condition A 75 Mg sustainea placebo 25 mg PPA Condition 6 25 mg PPA 25 mg PPA placebo Condition C platebii placebo 161

d. Clinical measurements. Measures Of blood pressure and pulse were obtained 9 times during each experimental zession: Once prior to initial drug administration (0 hr) and at 1/2 he; 1he, 2 he; 4 ht, 6 hr; 8 hr. 10 hr; and 12 hr following initialdrug administration. Blood pressure (sitting;

stanaing, supine) was measured using procedures recommended by the American

Heart Association (Kirkendall et al., 1980). 'Clinical measures of subjective

state wereobtainedusingvisual analogue mood-scales onwhichsubjects

indicated the extent to_ which they felt a drug effect and their subjective

impression of that drug effect. These measures were supplemented by

subjective reports of subjects and the observations of research staff.

2. Design

This study may be viewed as a 3 (drugtreatment conditions)x 9

(measurement occasions)mixed design. Mixeddesign analysis of variance procedures were usedto evaluate datafrom this component ofthe study.

Separate analyses were conducted for each of the dependent variables. Factors

in the analysis were drug treatment assignment (Condition A vs B vsC) and masurement occasion (0 he, 1/2 he;etC;); Treatment assignmentwas a

betwen-groups factor while measurement occasion was a within-subjects factor.

For alltests involving repeat:ad measures factor', a conservative F test was

used in evaluating statistical significance (see, e.g., Geisser 6 Greenhouse;

1958).

RESULTS

Specific results of the analysis of variarcefor each of the variables

studied are summarized below. 162

Pulse tended to increase slightly over the course of the session (F

16.67, 2 < .01) for 'subjects in all treatment conditions. No main effect for drug treatment was identified.

Standing systolic blood pressure was generally higher later in the session (F 4.34; 2 < .05) for subjects in all treatment groups.This trend was more marked for subjects in the placebo group (R 3.39; f<.05). NO main effect for drug treatment condition was identified. Standing-die-stale blood pressure was generally lowest at 8-10 hours post initial medication for subjects in all treatment groups (F 13.80; < .01). No main effects for drug treatment was identified.

Sitting systolic blood pressure was generally lowest at 1-4 hours post medlcation (F 4.01; < .05). Subjects in the 75 mg sustained release treatment Troup tended to show decreased sitting systo;i: blood premrelater in the session as compared with subjects in the 25 mg t.i.d. or ptacebo groups

(F 3;65;2 < .051. Sitting diastolic blood prev%41 was gefiLrally lower at 4-8 hours post dosing for subjects in all treaelwt s%oup CR 11.22; 4

.011; No main effect for drug treatment was IdentlfIed. These results are shown in Figure 1 (attached).

Supine systolic blood pressure was genera higher later in the session

(F 11.09; < .01). This increase tended to be largest in the placebo treatment group (F 4;44; < .05). No maln effect for drug conditioa was identified. Supine diastolic blood pressure tended to be lowest at 6-10 hours post initial doting (F 17;70; < .01). No main effect for drug condition was identified. 163

______Subjective measures of drug effect -add mesa( revealed no signifitant o.Jferences between thethree drug conditions. There were, however, significant changes in mood over the course of the session. These included measures of "drug effect" (F 8.53, P<.01), ratings of feeling "good" (IF

6.35; P < ;01); ratings of feeling "bad' (F 5.30,2 < .01), and ratings of drug liking (F 5.30i P<.01) over the course of the session. In general. subjects in all treatment groups (including placebo) reportedfeeling better

inthe (Merepleasurable) earlyin thesession and more dysphoric later

session; These variations in subjective state, although statistically reliable; were very small and were not considered clinicallyrelevant. Figure

2 illustrates these effects; Summary tables of means, standard deviations and analytiSof variance

resUltS for each variable studied are presented in theAppendix to this report.

DISCUSSION

The present study evaluated the acute effects of twodosage forms of

phenylprapanOlamine (75 mg ;.-stained release, 25 mg t.i.d.) incomparison with

(sitting, placebo. fleaSUres of drug effect on pulse, blood pressure

standing, and supine)and subjective state ("mood")were obtained over a

12-hour testing period;

NO significant main effects for drug treatment wereobserved on any of

was the measures. Differences in blood pressure between drug treatment groups treatments was very small. NO Consistent pattern of differences between arug receiving active drug observed. Oh tttemeasurement occasions, subjects

(3 164

treatments showed higher mean blood pressuresthan did subjectsreceiving placebo treatment. On other occasions; thiseffect was reversed. No

Statistically significant differences between drug treatments were foundon any of the measurement occasions.

As expected, statistically significant differences in blood pressure were found over the course of the daily session. Circadian va:iation of blood pressure is well documented (see; e.g.; Millar-Craig; Bishop; A Raftey; 1978).

Our results are consistent with this literature.

The present results also suggest that PPA; in the dosage forms studies. had no systemaz:o effect on subjective ratings of drug effect or drug likir;.

NO statisticalll, eliable differences between drug treatments were observed on measures V d effect or drug liking. The effects of the two PPA treatments were no',-ate° any better or any worse than that of the placebo. This findingis cusiStent with that ofSepprila; Nuotto; and Korttila (1981) in that no significant euonoeic effects were noted for subjects treated with FFA.

At was the case with blood pressure, subjective state ("mood") showed ;- -'- circadian changes over the course Of the session. In general; subjects in all treateent groups reported "b:Pr" early in the session as compared with later in the session.

Neon, the present findings suwt+ that phenylpropanolemine (in the dosage forms studied)is not associated with adverse effects on blood pressure, pulse, or mood. 165

REFERENCES

Dietz; A. J. Ampnetamine-like reactions to phenylpropanolamine. Journal of

the American Medical Association; 1981; 245; 6D1 -602.

Feceral Register; Vol. 47; No. 39; 1982.

Geisser; S.; & Greenhouse; S. N. An extension of Box's results on the use of

the F distribution in multivariate analysis; Annals of Mathematical

Statistics; 1958; 29; 885-891;

Hoebel; B. G. Effects of phenylpropanolamine (75 mg b.i.d.1 on ncrmotensive

volunteers; Personal communication; Thompson Medical Company. Abstract to

be published in Philacelohia Medicine; 1982;

Horowitz; J D. et al; Hypertensive responses induced by ohenylpropanolamice

in anorectic and decongestant preparations; Lancet; 1980; Jan 12; 60-61.

Kirkendall; N. M. et al; Recommendations for human blood pressure

determination by schygmomancmeters. Report of the Postgraduate Education

Committee; American Heart Association, 1980;

McNair, D. M. et al. Edits manual for the-Profile of Mood States. San Diego;

California: Educational and Industrial Testing Service, 1971;

Millar-Craig, M. W., BishOp, C. M., & Rairtey, E. B. Circadian variation of

Vood pressure.Lantiet, 197E, Avril 15. 795-796.

Silipala, T., Nuotta, E., & Korttila, K. Single and repeated dose comparisons

three antihistamines and phenylpropanolamine: Psychomotor performance

andsubjectiveappraisals of sleep. British Journal of Clinical

Pharmmce1o2t, 1981; 12; 179-188;

Silverman, H. I., at al. Lack oftide effects from orally administered

phenylpropanolamine and phenylpropanolamine with caffeine: A controlled

three phase study. Carrent Tlitraiieutit-Retearth; 1980; 28, 185-194; 166

AN EVALUATION OF THE ACUTE EFFECTSOF

PHENYLPROPANOLAMINE IN NORMAL VOLUNTEERS:

(CROSSOVER DESIGN)

Study Site: Behavioral Pharmacology Research Unit Johns_Hopkins University School of Medicine Baltimore_City Hospitals D-5-West 4940 Eastern Avenue Baltimore, Maryland 21224

Contact: F.Ink R. Fundeeburk Director, Clinical Consulting ANTECIL Inc. (301) 997-0880

Date: October 22 1982 167

FINAL REPORT OF CLINICAL PROTOCOL NO. 82-8(A)

An Evaluation_of_the Acute_Effects of Phertylpropanolamine_in Normal_Volunteers: (Crossover Design)

Sponsor: Thompson- Medical Company; Inc; 919 Third Avenue__ New York; NY 10022

Investigators: Ira Liebson_ George Bigelow Roland- Griffiths Frank Funderburk

Protocol dtveloped by: The Clinical Consulting Group ANTECH; Incand the Behavioral Pharmacology Research Unit

Contact: Frank Funderburk (301) 997-0880

Project Start Date:25-June-8-2

Project Completioi Date:a-August-82

esil 1

4 172 168

TABLE OF CONTENTS

ABSTRACT

INTRODUCTION 2 OBJECTIVE AND RATIONALE 3 INVESTIGATIVE METHODS 3 SUbJects 4 Design and Procedure 9 4 1; General Procedures 4 a; Subject Control 4 b; Meals and Food Restrictions 5 c; ,Dreg Administration 6 d; Clinical Measurement 6 2; Design

RESULTS

DISCUSSION 11 REFERENCES 12 APPENDIX 36 FIGURES

173 169

ABSTRACT

Fifty-nine (59)healthy normotensive volunteers (mean age = 05.5) participated in a double blind, placebo controlled crossover evaluation of the effects of a 75 mg sustained release dosage form of phenylpropanolamine HC1 on blood pressure, pulse, and mood. Each subject participated intwo experimental sessions; one under plae:to and the other Under the active drug treatment. Order of exposure to treatment conditions was randomly determined.

Measurements of blood pressure (sitting; standing; and supine)4 pulse, and subjective drug effect ("mood") were obtained 9 times during the session - at baseline (prior to drug administration) and at 1/2 hr; 1 hr; 2 hi.; 4 hr; 6 hi.;

8 hr; 10 hr; and 12 hr post-initial dosing;

Mixed design analysis of variance revealed no statistically significant

Main effects for drug treatment on:measure of pulse or mood. Nearly all blOtid pressure measures(the standingsystolic measure was an exception) thOWed statistically reliable - but clinically insignifIcant -differenccs betWeen placebo and the active drug condition; In all cases; the mean blood pressure was slightly higher under the active drug treatment; The magnitude of this effect, hOWeOr. wasextremely small (ths mean differences. ranged between .83 and 3.37 mm Mg).

As anticipated, most: measures showed main effects for time of day

(tirtidian effettt), Militating that the subjects'physiologicaland subjective state changed over the course of the session. These changes were, libWever, generally independent Of the drug treatment condition; This study suggests that the 75 mg sustained release dosage form of phenylpropanolamine has minimal= and clinically insignificant - effects on the blood pressure; pulse, or mood of normotensive indfv!dUd1S;

174 170

An Evaluation of the Acute Effects

of Phenylpropanolamine in NormalValunteert!

(Crossover Design)

INTRODUCTION

PhenylOrtipanolamine hydrochloride (PPA) is a syntheticcompound with actions similar to ephedrine; However, PPA is generally believed to produce less CNS stiftlitiOn than ephedrine; PPA is currently marketed oier=the- counter (OTC) in the United States inboth as a nasal decongestant and as a weight control aid. Retently the FDA and others have raised questions about the safety and appropriateness Of OTC evOi.oflityof PPA (Feceral-Reoister.

Vol. 47, No. 39, 1982; HOrtiWitl, 1980; Dietz; 1981;Lancet, 1982). In their publication, the agency requested additional information onthe effects of PPA on a variety of safety parametersincluding blood pressure, pulse, and self- design reported side effects. In the present report, crossover experimental was used to compare the effectsof 75 mg sustained release PPA with placebo on Fifty-nine normotensive adults were studied over atime these parameters. course of 12 hours.

OBJECTIVE AND RATIONALE

This study was designed tO extend previous researchconduced in our laboratory (Funderburk at al., 1982). In that investigation, 150 normotensive adults participated in a study comparing theeffects of two dosage forms of

PPA (25 mg t.i.d., 75 mg sustained release) withplacebo. No significant main the measures of blood effects for drug treatment werefound on any of in that pressure, pulse, or mood. Although the relatively large sample size

175 171

study provided considerable statisticalpower; it was believed that an even

more sensitive comparison would be afforded by a crossover study in which each

subject would serve as his own control.

Several studies haveinvestigated the acute effects of PPA innormal

subjects (e.g.; Silverman et al.; 1980; Hocbel; 1982). However; these studies

have generally involved rather small subject samples and have; therefore; had

relativelylow statistical power. Therecentstudy inour laboratory;

however; (Funderburk et al.; 1982) which employed 150 subjects in a parallel

groups design provided a rather powerful test of the effects of PPA or normal

subjects; The present study; using a crossover design; was implemented to

provide an even more powerful evaluation of PPA effects in a large group of normal volunteers;

INVESTIGATIVE METHODS

Subjects

Subjects 4re 59 normalvolunteers (both male andfemale; mean age =

25 ;5); The study population consisted of 33 caucasians; 25 blacks; and 1

American Indian. All has given informed Consent and had been screened to meet the following criteria:

a; between 18-55 years of age

b. no current use of medications which would compromise the validity of

the evaluation of the test products

c. no physical contraindications to consumplion of PPA at the dose levels

used in this study

d. no history of severe emotionaldisturbance; chronic alcoholism; or

drug a:use

71 176 172

e. evidence that the subject would participate in the research and be

cooperative

f. good general health based on a medicalhistory interview conducted

Within one month of the study start and a recent Oysical examination

9; female subjects certified that they were not pregnant or nursing a baby for the duration of the protocol.

Design And Procedure

ibjects nee randomly assigned to one of two treatment sequences. One group (n 30) received the placebo treatment on their first testing occasion and the 75 mg sustained release treatment on the second testing session. This order of treatment was reversed for subjects in the other group (n 29). The two treatment sessions were always separated by at 'least one washoutday to oiniinize any possible treatment carryover effects. The basic investigative procedures fdll6Wed Mr each subject are detailed below.

1. -General Procedures free of all a. bl°ct Subjects were instructed to be medications for the week prior to the first administration of a testproduct.

Subjects who had ingested substances which compromised the validityof the study were excluded. Study medications were administered under clinical supervision, SubJecti reivained et the test facility for the entire testing period during test days.

b. Meals and food-restrIct4ons. Oh test days subjects were provided with e choi,:e of standard noontime meals. Foods containing xanthines (e.g.; coffee; tea; cola) were not permitted on study days.

177 173

c. Drug administration. In this investigation a currently marketed dose of a test product containing PPA (75 mg sustained release PPA)was

compared with placebo. 01 each test day subjects receive' three administrations of a test product (either active medication or placebo). Doses were

given at 4 hour intervals (e.g., approximatelyB:DD am, 12:C0 noon, and 4:00

Subjects were randomly assigned toone of two treatment conditions on the first test day; Dne group of subjects (Groun !-.) received the 75mg sustained releaseproduct attheir first dosing and matchingplacebo capsuleson subsequent dosiiigt. The other group (Group B) received placeboat all three dosings. After at leatt one washout day, the subjectsreturned to complete

the second leg Of the crossover. During this session; they received the treatmentnot adminittered on the firstday. This dosing schedule is illustrated in Table 1.

Table 1

Dosing Schedule

Dose 1 Dose 2 Dose 3

(approx. 8:00 am) (approx. 12 noon) (approx. 4t00 01

Settibh Group A 75 mg sustained placebo placebo One Group 8 : placebo placebo plitebo

Session Group A placebo placebo plittbo

Tido Group B 75 mg sustained placebo 019-cebo

178

27-936 0 - 84 - 12 174

Measures of blood pressure andpulse were d; Clinical measurMmemtt. Once prior to initial drug Obtained 9 times during each experimentalsession: 1 he; 2 hi.; 4 hr; 6 hr, 8 hr, 10 hr. and administration (0 hr) and at 1/2 hi., Blood pressure (sitting. 12 hr following initial drugadministration; procedures recommended by the American Standing; supine) was measured using Clinical measures of subjective Heart Association (Kirkendall etal., 1980). Thz4v measures Hite Were obtained using analogueratings Of drug effects. subjective reports of subjects and theobservations of were supplemented by research Staff;

2. Design Thit sttoy may be viewed as a2(drug treatment Conditions) x 2(orders

9(measurement occasions) mixed design. Mixed of treatment administration) x fraM this design analysis of varianceprocedures were used to evaluate data Separate analyses were conducted foreach of component Of the investigation. Factors in the analysis were drug treatmentcondition the dependent variables. order of treatmentadministration (75 mg sustainedreleasevs. placebo), occasion (0 (active dMUg first vs; placebotreatment first); and measurement Order of treatment adainiStration was abetween groups hr. 1/2 hr, Ott.); measurement occasion were withinsubject factor while drOg treatment and _ repeated measures factors; aconservative F factors. For all tests involving statistical significance (see; e.g.,Geisser test was used in evaluating

Greenhouse. 1958). RESULTS analysis of variance for each of thevariables Specific resultt Of the

studied are summarized below.

179 175

Pulse tended toincrease slightly over thesessionsheWing a peak at

approximately 6 hours post-dosing (F 9.45,2 <.01). This effect occurr=d

under both drug treatment conditions. No main effect for drug treatment was

identified. No other main effects or interactions were identified.

Standing systolic blood pressure was relatively stable for subjects inboth

/drug treatment groups; No main effects or interactions were identified.

Standing diastolic blood pressure tended to be slightly higherunder the

active drug treatment than under placebo. Although this effect was

statistically reliable (F 7.41; 4 .01), the overall magnitude of the effect

was small(mean difference between treatments= 2.26 mm Hg). Under both

treatment conditions; Standing diastolic blood pressure tended to show peaksat

4 and 12 noues nest-initial dosing OF 6.81,2 <.01). Sitting systolic blood pressure tended to be slightly higher under the

active drug treatment than under placebo (IF = 4.46,2 < .05). The mean

difference between treatments was 2.09 mm Ng. No other main effects or

interactions were identified.

Sittilig-d-1-6-Steli-e bleed pros tended to peak at 4 and 12 hours

post- initial dosing under both treatment conditions(F = 5.26;2< .05).

Overall, sitting diastolic blood pressure tended to be higher under the active drug treatment than under placebo OF 11.28,2 <.01). The mean difference between treatments was 2.75 in 4g. No ether main effects of interactions were identified.

SUpiiiisystral-to blood pressure tended tn peak at 4and 12 hours post-initial dosing under both treatment conditions (F= 7;33; <;01); The peak effect at 4 hours was most evident for subjects underthe active drug

180 176

;05); treatment (resulting in a drug xtimeinteraction. if 4.10. t

Overall; supine systblic blood pressuretended to be higher under the active The mean differecce drug treatment thin under placebo(F 7.5; < .011. ,ructions were between treatments was 2.52 ram Hg. No other main effects c- identified. Supine diastate blood pressure tended topeak at 4 and 12 hours post- Overall. initial dosing under both treatment conditions(F 6.22;2 < .05). drug Supine diastolic blood pressuretended to be higher under the active

treatment than under placebo UV 11.91;1 < .011. The mean difference betuvn

siiip,tly treatments was 3.37 mm Hg. The time course of this drug effect was No other main effects different for the two treatment ordert(4;15; < ;05);

or interactions were identified. Subjective measurescrfdrugOffett and moodrevealed no siiicent

differences between the drug treatmentConditions on any cf the measLres __ 'feeling ttOded (raring of 'drug effect.'rating Of 'feeling pod;' rating of Ratingi Of 'drug effect' tended to peak at bid,' and rating of 'drug liking'). No approxliately 6 hours post-initialdosing under both treatment groups. identified for any of the subjective other Main effects or interactions were

measures. deviationa. inn enulytis or varltrce SIMMilry tables of means. standard presented in the Appendix to this -eport. resiiItt for each variable studied are

DISCUSSION sustained release The present study p red the acute effects of a 75 &g A crossover dosage Or Of pheny ,h7,1-4ine in comparison with plotebb. Measures of derign. n rnlch 060 iabject ;:,..ved as his owncontrol. was used. 177

drug effect on blood pressure (sitting;standing, andsupine' and

subjective state ("mood") were obtained over 7 12-hour testing period.

Atin our previously reported study (Funderburk et al., 1982), overall

differences between phenylpronnnolseneand placebo onmeasuresof blocs

pressure werevery small. in the present study,however, statistically

reliable differences between the active drug and placebo were identified. This

result can be attributed to the increased ftatistical power of the present

design. As compared with our previous invcstigation; the present study had

both a larger sample size per group (n .9 vs. n 50) as well as alower

overall error variance (a result of using each subject as his own control);

Both of these features of the design served to increase statistical power.

Unoer such conditions; it is quite possible to ,Oentify statistically reliable effects which are clinically trivial (see; e.g.; Cohen; 1965). In the present

study,for example; mean blood pressure differences between druy treatme^t conditons ranged from.83 mm Hy (steno:ng sysl'olic) to 7.37 mm Hg (supine diastolic) with an average overall difference of less tnan 2 mm Hg Obv!put.ly; such small overall effects are not regarded IS clinically significant.

As expected; statistically significant difftrenCes in blood pressure were generallyfound overthe courseofthe daily session. Thisfinding is consistent with the literature on circadian variation of blood pressure (see,

*.9-. Bock E Kreuzenbeck; 19t- Millar-Cralg it al.; 1978; Pichardson it al.;

1964; RoS;19801. Drug treatment did not appear to affect thesr normal

Orcadlan vOriations, MIS result is consistent with our previous report.

The pretert stuCy rerliczted our previOus investigation with. ,ve(L to st.tjr:t.v( wily( *.- Overall our analysis failed to ,vr.t am

182 78

drug treatments on subjectiveratings of Systematic differences betvken the not rated as any drUg effect or drug liking.The effeCt of tNe active drug was Somewhat less circadian better or any worse than thatof the placebo. observed in this study as compared with variability in subjective effect Wit

our previous investigation. the Overall; the results of the presentstudy are quite compatible with Although statistically reliable resultt presentedin our previous report

effects on blood pressure were notedfnr the 75 mg sustained release dosage effects Were eltremely small and were not form of phtnylpropanolamine, these Likewise. no adverse effects werenoted on considered Clinically relevant.

pulse or stibjettive state. and in More comprehentive work is neededin the area of PPA effects on mood physiological and psychologicaleffects ofthe Ole relatienthip between the future investigatio- inclOdean evaluation of PPA drug. Other areas for obeseland effects on specialized patientpopulations (e.g., hynertensivel;

over a wider range of dOset 179

REFERENCES

Bock;K. D.; A Kreuzenbeck,W. Spontaneous blood Pressure variations in

hypertension: The effect of antihypertensive therapy and correlationswith

the incienoe of complications. In F. Gross (Ed.), AntAtypertensive

therapy: Principles and _or

Springer. 1966;

Men, J. Statisticelpoweraalys-i-sforbitravioral sciences. New York:

Aeademic Press, 1969.

Dieti, A. J. AMphetamine-like reactions to phenylpropanolamine. Journal of

-theAmeff-ce-nYedical As-sociation, 1981, 24 601-602.

f441or.,1 Revster, !ol. 47. No 39. 1982.

Funderburk, F.R., et al. Effects of phenylprow .olamlne on blood pressure;

pulse, and mood. Report IA, Thompson Medical Company. October 8; 1982.

Geisser, S., S Greenboe, S. W. An estension of Box's results on the use of

the I distribution in multivariate analysis. Annals of ;onhematiral

Statistics, 1958; 79, 885-091.

lioebel, B. G. Effects of phenylpropamolimine mp On liOnhOithi1V0

volunteers. relsonal communication; Thrown Medical Company: Ahttrat to

hr 'WM I ShirilIn 1'011 &die' (hla MOM( 1.0, 1987.

tioruwiti; ti. el AI. 8K)Artensive M11011014 induten by phenylprodanolaminv

1n anore(lit end Or4ongetflifft preparations. tans -is 19110, 60-61.

Kirkendall, N.N.et al. NIcomevfndationsfor hussan-btoodpristvz:Ivormina.

11b'> sphyrwsui Wffpnet of the Postgraduate idulation :cor-111 l;.44.

haw. nee' fa. i"." ".10. :.1 P.,TIMANPInr t,Ve;the anuntel. Awl,

Iv0 :;:)

t..10 PI 4 11100V. ( A liar,, li ( fellatio. of 1.0o

peels.. towelAli/ ..14 '40

Aliholdsoo, 0 A ffintoo, Sl r,ll, 1 &

P., Iii Ii.,. I. 4.44.141 reftinei41.1.00.1 100 di, 404 010( kilifik,0

$000iie, 1004. N. 450 AAO

11,11., 4 1We 10e&fniewn; of 01,.1 ...fowl. I. A J licit chill A 11 W 04.

Itaft I thy htilisan.i.. vatians roman r444'!. 10011. PP. Sr *11

" 1 el -I +mti of Oa. offylts fsom sominilla.ed

rh..0...pan0100104, moth fiftletele h to11.,1100

1,,08 l,119 Ilialtt Nlli. 11101410, 100o, to, INA :V4

1 &4 180

Supplement to Clinical Protocols

82 -8(A) and 82-8(8)

(75 mg) EFFECTS ON EVALUATION OF PHENYLPROPANOLAMINE

STANDARDIZED MEASURES OF DRUGEFFECT AND AFFECTIVE STATE

Behavioral Pharmacology ResearchUnit_ Study Site: School of Medicine The_Johns Hopkins University Baltimore_City_lipspitals D=5=West 4940_Eastern_Avenue Baltimore; Maryland21224

Contact: Frank R. Funderburk Director. Clinical Consulting

(301) 997-0880

Date. DecembeR 6. 1982 181

SUPPLEMENT-TO CLINICAL PROTOCOLS 82=8(A) and 82-8(8)

Evaluation of-Phenylpropanolamine_Effects_on Standatdited Measures of Orng Effect and AffectiveState

Sponsor: Ili-moon Medical Company; Inc; 919 Third Avenue New York, NI10022

investigators: Ira Liebson George Bigelow Roland Griffiths Frank Funderburk_ Aliseair Mackenzie

.;,rotocol developed by: The ainical ConSUlting Group PITECN, Inc.- and the Behavioral PharMacology Research Unit

Contact: Frank Funderburk (301) 997-0880

Date: Dectotet 6, 196E

186 E 0:e.Or TENTS

PSTRACT

INUODULTION 7 INVESTIGATIVE METHOOS

Subjects rif. 4 2 Design and Proreaure 2 I. AdJittitia Research C-aterInventory (ARCI) 3 2. Profile of Mod Stat*Is(F0147.) 4 Statistical Analysis 4 RESULTS 4 Parallel Groups Delign 6 Crossover Design

DISCUSSION -12 REFERENCES 183

ABSTRACT

Additional analysis was undertaken on data collected as part of

Clinical Protocols 82-8(h) and 82 -8(B).These analyses focused on a comparison of subjective IPA effects with those of other CNS-active drugs and a more rigorous evaluation of PPA effects on affective state ("mood").

These an4.1:les indicated that PPA, in doses of 25 mg t.i.d. or 75 mg sustained release, were not associated with euphoria, amphetamine-like reactions, or sedation. Some evidence was found which suggested_that

PPA functioned to reduce the fatigue and boredom associated with a

12 hour experimental session in a relatively onstimulating environment; 184

INTRODUCTION

Previous reports from our laboratory (Funderburk etal.; 1982a, 1982b) examined the effects of phenylprbOandlaffiihe (PPA) onblood pressure, pulse, and mood 'including subjective ratings Of drugeffect) in normal volunteers.

Ill a large sample (N = 150) parallel groupsdesign study; PPA doses of

25 mg t.i.d. and 75 mg sustained release were feUnd tohave minimal effects on clinical measurements of blood pressure,OUltd; Or Subjective ratings of drug effect and drug liking over a 12-hour eXPeriffiehtailsession: The author, concluded that PPA at the dose levels studied was ittassociated with adversc effects on the clinical measures studied. This CohtlUtitin received further

Support in a statistically more PnWr. ssover study (N . 59) which cOMpared the 75 mg sustained releasi: -v. :lon with plat-ebb on these same measures:

The present report is a supplement. tJ Protocols82-8(A) and W-8(8).

It describet additiOhal analysis undertakento provide additiohal infer-nation on the subjectii)z effeCIS of PPA; Particular attention will be focused on two key issues of concern: (1) A comparison of PPA with other CNS4CtiVe drugs and (2) A more rigorous evaluation ofPFA effects on affective state derived from widely used ("noel"). In both instances our measures will be and well standardized osychometrit instrumentswhich have been proven

sensitive to the effects of CNS drugs.

INVESTIGATIVE METHODS

described in Subject'i. Subject characteristitt are identical to thos.: normal our previous reports. In the parallel grcrips design 150 healthy 185

subjects participated (N 50 in each of three expey';. -4), /

the crossover study 59 healthy normal subjects participated (each being

exposed to each of two experimental conditions).

cesion at Procedure.

The measures described in this report were obtained from subjects who

participated in Clinital Protocols 82-8(A) (parallelgroups design) and

82 -8(B) (:rostever design). Two standardized test forms were administered

subjects prior to each clinical measurement occasion. One form was a

Short version of the Addiction Research Center Inventory (ARCI) Th'' test

allows comparison of PPA subjective effects with those of other CNS-active

drugs. The other form was the Profile of Mood States (POMS). This test

allows an evaluation of changes in affective state associated with drug

treatment. Each form generally required less than 5 minutes to administer.

More detailed descriptions of these tests follows:

Addict-ionResearchCenter Inventory (ARCII; Detailed description of tte

ARCI scales was given by Haertzen (1974): The empirical drug scales on thit inventory were developed by racing items which differentiated placebo from A variety of drugs 'including morphine, pentobarbital, Chlorv.vmazine,

LSD, amphetamine, pyrahexyl; and alcohol. In Addition, clusters of items were developed (group variability scales) Which combined items from 'the various scales to reflect patterns of drug effects. The scales used in this study, and the Characteri;tics which they reflect are:

'90 186

similarity to (1) AMP: empirical scale which measures

amphetamine effects. whith measures similarity (2) BG: ow variability scale Interfteted as a measure to benzedrine effects.

Of intellectual efficiencyand energy.

group variability scale whichitatiitts a (3) MBG: Interpreted es a Worphiiit-benzedrine effect.

measure of euphoria.

measures (4) PC G: grou0 Vailability scale which

pentobarbital- chlorpromazine - alcoholeffectt;

Interpreted as a measure of sedation,fatigue,

and low motivation. similarity to LSO (5) LSD: empirical scale which measures

effects. Interpreted as a measure of anxiety,

tension, difficulty in cOncentratick

depersonalization, and psychomimetiichanges.

Also interpreted as a measureof ep.phoria.

of Profile of Mooc States (PM. The POMS FCalon -,:;,,Ade a means

This s:-Wes were developed assessing transient, fluctuatingmood states. including by factor analytic methods in avariety of subjett .,!%*1111ations populations fee; MtNairi Lori',and both normals and speCialized pttient discussion of the developmentof Droppleman, 1971, fei a more detailed sensitive measure of the these scales). The P1MS has been found to be a drug administration) effects of various experimentalmanipulations (including identifiable mood or affective Inmal volunteers.Th6 PUS measures six 187

states as well as various specialized affective states and global mood.

The scales used in ',`:is study were:

(1) Ten.. lety

(2) Depression-Dejection

(3) Anger-Hostility

(4) Vigor -Activity

(5) Felgue-Inertia

(6) Confusion-Bewilderment

(7) "Friendliness"

(8) Total Mood Disturbance.

Statistical Analysis. Data were analyzed using mixed design analysis of

variance. Separate analyses were conducted for each of the dependent variables.

In the parallel groups design factors in the :v.:: *Itiff-, 44410 treatment

assignment (placebo; 25 mg t.i.d., :Pl.:ase) and measurement

occasion (0 hr.1/2 hr. etc.). Trio ignment was a ba:meen-group factor

while measurement occasion was a within- subjects facter. FactorS in the

trassover design were dfbg treatment assignment, order of treatment

administration (placebo first vs. active drug first), and measurement occasion.

Order of drug administration was a betWeen groups facter while drug treatment

and measurement occasion were Within subject factors. In both analyses tests

involving repeated measures were evaluated using a conservative -F test

(e.g., Geisser and Greenhouse. 1953).

Resu'ts: Parallel Groups Design

Specific results of the analysis of variance for each of the varisbles studied are summarized below:

188

ARCI Variables identified. AMP. No main effect for drug treatment condition was

A significant main effect for measurementOtcaSion was found (F = 3;91; p4;05) reflecting a general decrease in AMP scores overthe session for subjects in all treatment groups. No signifiCant interactions were identified:

identified. BG. NO main effect for drug treatment condition was

A significant main effect for measurementoccasion was found (F = 4;80;

04.05) refletting a general decrease in 13G scores over thesession for subjects in all treatmenr groups. No significant interactions were identified.

identified. maG. NO Significant main effects or interactions were

for drug PCAG. No main effects or interactions were found occasion was treatment. A significant main effect for measurement

identified (F = 7.46, p<0.01) which reflected atendency for sedation

(PCAG score) to be lowest early and late in thesession as compared-

with the middle of the session. This general trend was present in all

drug treatment groups. No other main effectt or interactions were

identified.

POMS Variables interactions were Tension-Anxiety. No significant main effects or

identified:

interact-ors Dateessnn-De4oc-.ion. No slenIficant main effects or

were identified.

*Lsu. No significant r. is c::ects or interactions were

193 189

Anger-Hostility. No significant main effects or interactions were

identified.

Vigor-Activ4ty. No main effects or interactions were found for

drug treatment. A significant main effect for measurement occasion

was identified (F = 10.37. p<0.01) reflecting a general decrease in

vigor over the course of the session. This general trend was present

in all drug treatment groups. No other main effects or interactions

were identified.

Fatigue Inertial-. No significant main effects or interactions were

identified.

Confusion-Bewilderment. No significant main effects or interactions

were identified.

"Friendliness." No main effect for drug treatment condition was

identified. A significant main effect for measurement occasion was

found (F = 19.98, tr<0.01) reflecting a general decrease in "friendliness"

over the course of the session for subjects in all 'drug treatment groups.

No significant interactions were identified.

Total Mood Disturbance. No significant main effects or interactions

were identified.

Results: Crossover Design

Specific results of the analysis of variance for each of the variables

Studied are summar:el below:

194

27-436 0 - 84 - 13 190

MCI Variables

AMP NO significant main effects or interactionswith drug

treatment were identified; A significant main effect for time course wet identified (F 3;14; pg(L°S) which reflected a general decrease

stores over the Course of the session for subjects inboth drug

'meatment groups.

ECG: NO significant main effects or interactions with drug

re Owe were identified. A significant main effect for time course

oar, ir.ntified (F 3;56; p4;05) which reflected a general decrease

in scores oven the course of the Session for subjects in bothdrug

;treatment groups,

i4. No significant main effects or interactions with drug

treatment were identiflen. A significant main effect for time course

w identified (f-= F.4). p<0.05) whichreflected a general decrease

in scores over the session for subjects in both drugtreatment groups.

identified PCAG. A significant main effect for drug treatment was

(F 4.97i p

(reflecting 7c s fa.,i:ue) under the 75 mg PPA treatment as compared

with placebo. This effect was stronpst in subjectS Whe received the

75 mg PFA dose in their seconu session (F = 5.72;04;02); A main

effect for time cour,e was also identified(F 2.57; 04;05) which

reflected a general increase i% PCAG scores over the courseof the

Session for subjects in both drug treatment groups.No drug k time

thteactiom was identifed.

1 95 191

LSD: A significant main effect for drug treatment was identified

(F = 7.69; p<0.01).overall subjects reported lower LSD scores

(reflecting less dysphoria) under the 75 mg PPA treatment as compared

with placebo. NO other main effects or interactions were identified;

POPS Varieiles

Tensi-r ..7kaiet,... A main effect for drug treatment was identified

(F = 4.8b, Overall subjects obtained lower tension and

anxiety sc, ! leer the 75 mg PPA treatment as compared with placebo

treatment. No other main effects or interactions were identified.

Depression-Deietti-on. No significant main effects or interactions

were identified.

Antrer--Hos-t-i-l-i-tv-. A main effect for drug treatment was identified

(F = 5.27; p<0.025). Overall subjects obtained lcwer anger-hostility

scores under the 75 mg PPA treatment as compared with placebo treatment.

No other main effects or interactions were identified.

Vidor-Activity. No main effects or interactions for drug condition

were identified. A main effect for measurement occasion (F = 5.23,

p<0.05) was identified which reflected a general tendency for subjects

to obtain lower vigor-activity scores over time. No other main effects

Or interactions were identified;

Fatioue-Inertia: No significant main effects for drug treatment;

Order, or tire course were identified. A drug x order interaction

(F = 964: si'0.01 was ;eantiFics which reflected the 'act that grPiti,r F,:t'guc was rcPcrted under placecc as cpposee to 75 mg PPA In

el 196 192

one group of subjects while theopposite trend was present in the other identified. group of subjects. No Other significant interactions were

A significant main effect for drug Confusion -Bewilider6eht;

condition was identified (F . 7.00;041;01); Overall subjects obtained

undet the 73 mg PPA treatment than lower Confusion-Bewilderment scores identified. under placebo. No other main effects of infc actions were

interactions with "Friendliness." No significant main effects or

drug treatment were identified.A significant time course effect was

fOUnd (F = 6;62i pc0.01) which reflected ageneral tendency for

"friendliness" to decrease over the course ofthe session; although

ftithdliness scores did tend toincrease at the last measurement

occasion.

TOW ?Mood Disturbance. No significant main effettt Or interactions

were identified:

DISCUSSION

The present study evaluated the acutesubjective effects of two &sage forms of PPA (75 mg sustained release;25 mg t.i.d.) in comparison with These assessments were repeated in a placebo in a parallel groups detiga; With crossover design wnich tompAtedthe 75 mg sustained release dose comparison of PPA effects with those placebo. Measure' obtained ihtlUded a effi-.7t; as well as an evaluation of PPA of a variety of CNS-active drug effects on various affp"Ove states. 193

In the parallel groups design PPA effetts were not different from those

of placebo on any of the measures studied. Subjects in all groups tended

to feel more sedated or tired as the session progressed; with lessening of

the sedative effect prior to the conclusion of the session; The extent and

nature of this effect was not related to drug treatMent.

:al the more powerful crossover design some statistically reliable

differences between the 75 mg sustained release PPA treatment and placebo

were identified. In particular, on the ARC1 scales the 75 mg PPA treatment

was associated with less sedation-fatigue and less dysphoria during the

course of the session as compared with p'acebo. However, no evidence of

amphetamine-like effects or euphoria was found. As expected, most measures

showed reliable circadian effects over the course of the session. As in

our previous studies, these effects indicated that subjects generally felt

"better" early in the sessions as compared with later in the session.

The POMS measures provided further confirmation of these effects. Subjects

reported feeling less tense or anxious, less hostile, and less confused

under the 75 mg PPA treatment as compared with placebo.

The pattern of results in the present study is consistent with tnat

found in our previous analysis of PPA mood effects (Funderburk et al:, 1982a

1982b) and with the findings of Seppala et al. (1981). Overall no reliable euphoric effects were noted for PPA. although there is some eldence that

PPA functionee tb reduce the dysphbria and boredom associated with a 12-hour experimental session in the restricted and relatively bland environmental setting of a rnsearcn laboratory. 7,--us,it accears that PPA tay serve to

meta 7:ler:nes: and recuce fati.:e in relatively unst.culating

198 194

In the doses st;:died PPA dia not pro,!uce a pattern ofsubjective effects which would be indicative of high abuse liability. The absence of euphoric or amphetamine-like effectt or s!.!tive-typeeffects suggest that PPA is not likely to be kok,,ingly chosen as a drug for self-administrationby someone seeking Such psychological effects. Such an interpretation is consistent with our previous finding that ratings of "drug liking"for PPA were not different from those o' placebo.

Overall the present findings suggest that PPA may have mildlybeneficial effects no affective state in that it increases alertnessand reduces

Further dysphoria. The magnitude of these effects, however, is not large. thete findings may be limited to affective states measuredunder unusually low levelt Of cnvironmental stimulation. At the same time, no evidence of amphetamine -like or euphoric effects were noted even inthe more Powerful crossover design.

199 195

REFERENCES

Bigelow, G.E. et al. Development of clinical procedures for abuse liability

assessment: Progress report from the Behavioral Pharmacology Research

. Unit of The Johns Hopkins University School of Medicine and Baltimore

City Hospitals. In L. S. Harris (Ed.) Problems of Drug Dependence 198Z:

Prikeedings ofthe- 44th-

Proleam-of-DrugDependenee. National Institute on Drug Abuse Research

Monograph Series, 1982.

Funderburk, F. R. et al-. Effects of phenylpropanolamine on blood pressure,

pulse, and mood: Parallel groups design. Report to Thompson Medical

Company. October 8, 1982. (a)

Funderburk, F. R. et al. Effects of phenylpropanolamine on blood pressure,

pulse, and mood: Crossover design. Report to Thompson Medical Company.

October 1982. (b)

Geisser, S., and Greenhouse, S. W. An extension of Box's results on the

use of the F distribution in multivariate analysis. Annals of Mathematical

Statistics, 1958; 29; 885-891.

Haettlen, C. A. An overview of Addiction Research Center Inventory Scales

(ARC!): An appendix and manual of scales: Washington, D. C.: National

Institute on Drug Abuse; 1974: DHEW Publication No. (ADM) 74-92..

McNair, 0: M. et al. EDITS manual for the Profile of Mood States.

San Diego. CA: Education and Industrial TeSting Service, 1971.

Seppala, T. e-t al-. Single and repeated dose comparisons of three

an4ihistamines and phenylpropanolamine:Psychomotor performance and

subjective appraisals pf sleep.Oritisl, Jaurnai of Clinical Pharmacology;

1981, 12, 179-188.

°'-10 196 Ms. OAX/ik. Thank you, Doctor. Dr._ SILVERMAN. Thank you Next we will hearfroth My -Col= league; Dr. Coons, professor of psychology at NewYork University. Dr. Coons? STATEMENT OF EDGAR COONS Dr. COONS. Good afternoon. My name is EdgarCo tins. I hold a Ph; D. degree in psychology from Yale._I am a professorof psychol- -NY at NOW York University and a former chairmanof its psyCholo- gy department. My research specialtyis physiologiCal psychology. I have with nib Written testimony on my research onphenylpro- panOlainine [PPA] which I would like to submit for therecord. Dr. COONS: I would also like to present to you themain ppints cif that testimony. In my research I used rats who were implantswith electrode in the_part of the brain that controls boththe appetite and the feeling of reward. When electrically stimulated,these rats would begin tb feed even when thoroughly satiated: Pretteatment of these rats with PPA significantly increasedthe amount of electrical current required to makethe rats eat, showing the effectiVeneSS of PPA as an appetitesuppressant Rats can also be trained to stimulate themselveswith the cur= rent to produce a feeling of reward.PPA did not decrease the amount of current needed for reward, indicating thatit had no re- Warding or behavioral stimulant properties of its own. This result was markedly different when d=amphetamine was used That drug greatly decreased the amountof_current needed for sell-stimulation, indicating that contrary toPPA, d-_arnphet- amine; while also an effective appetitz_suppressant,has considerable Stimulant or euphoragenic properties: Animal studies provide very useful, objective evidenceof the effectiveness of appetite suppressants because, and this isimportant; aniinalS are not affected by such factors as advertising,motivation, or the social pressures to bethin. My studies With rats lead me to conclude that PPA is an effective appetite suppressantthat has no stimulant or euphoragenic properties. Thank you. [The prepared statement of Dr. Coons follows:]

PREPARED STATEMENT OF EDGARE.COONS, PH.D., PsorEssos orPSYCHOLOGY, NEW YORK UNIVERSITY Goad morning. My name is Edgar E. Coons. I hold a Ph. D.degree in psychology. I am a profetsor-of psychology at New YorkUniversity and the former chairman of its Psychology Department. My research specialty is physiologicalpsychology._ I have been actively involved in the study of appetitecontrol mechanisms since 1957,_ when _I discovered that a region of the rat brain; thelateral hypothalamus, can produce feelings of hunger orfullness, as well as euphoria when electrically stimulated. Rats and other animals are very useful models forstudying the effects of appetite suppressants because they provide objectiveevidence of changes in feeding behavior and weight loss since-animals are not affected bysuch factors as adver- tiaing, orthe social pressure to be thin._ The stud- I would like to report on today - compared theeffects of phenylpropanolamine IPPA) and d-amphetamine, a well-known appetitesuppressant, on the feeding and reward-seeking bahavior of-rats. Four rats in which the lateral hypothalamus waspermanently implanted with an electrode and then electrically stimulated were usedfru _the experiments. If food was present end -the current turned ona-thoroughly satiated rat would immediately begin to eat and would continue to ea fo long as the current lasted: 197

By varying the rate at which these electrical pulses were presented, the number of pulses per second necessary to get the thoroughly satiated rats to begin "ating within 20 seconds after the current was turned on was determined. Next, the number of pulses necessary whefl rats were pretreated with doses of PPA ranging from 0.82 to 33.0 mg/kg was determined. At doses of 16.5 and 33.0 mg/kg, PPA markedly increased the number of pulses per second required to induce the rats to begin eating, thereby demonstrating the effectiveness o; PPA as an appetite suppressant. Whether or not PPA induces euphorogenic effects that mightlead to the development of drug dependency was evaluated in the same four rats. Rats will voluntarily press down a lever to self=administer brief bursts of current to the reward system that runs through the same lateral hypothalamic region involved in controlling the appetite. Thus, by varying the rate at which electrical pulses of a constant intensity were presented, it was possible to vary -the sense of reward. By arranging it so that each time a rat pressed the lever he obtained a 0.25-second train of pulses, it was possible to determine how many pulses in this train it would take to reward the rat enough to press the lever at least 20 times a minute. The effect of PPA on the number of pulses required was determined using the same dose range and methodology as in the tests of appetite suppression: It was found that the number of pulses required to be rewarding did not decrease as the dose of PPA increased and may have actually increased slightly. This demonstrates that PPA has no ability to provide a reward, in contrast to d-amphetamine. When the rats were treated with d-amphetamine, the amount of current required for rewarding was greatly decreased, indicating that d-amphetamine was providhig much of the reward itself. In the appetite suppressant tests, d-amphetamine greatly increased the amount of current necessary to elicit eating, confirming its appetite suppressant properties. It was concluded that whsle d-amphetamine markedly suppressed appetite at doses even lower than those required for PPA, it also markedly potentiated reward, perhaps even to a euphoric level. In contrast, no dose of PPA tested potentiated reward, although PPA, like d-araphetamine, decreased appetite. These findings are in agreement with the studies conducted by Prof. Bartley G. Hoebel of Princeton University in both rats and humans, which found that PPA was an effective appetite suppressant with- no euphorogenic- properties. In his human studies, which were published in 1975 in the journal Obesity and Bariatric Medicine. Hoebel did not observe any stimulant or other adverse effects in the subjects. In conclusion, based on my own studies and similar studies by Hoebel, phenylpropanolamine is an effective appetite suppressant that does not induce any central nervous system stimulation or euphorogenic effects. I ask that my comments and a copy of the study I discussed be entered into the record. Thank you.

202 1. 198

Coons, E. E. Exhibit

A; HOebel, B. G. et al.i_Body Weight_Deareased in Humans By Phertylpropanolamine Taken Before Meals, Obesity/Bariatrie-Me& Vol. 4, No. 5, 1975 Bartle) G.Hurbel., brig K. Krauss,' JoelCuup:r, and &nut tt'siissii:

Body Weight Decreased In Humans By Phenylpropanolamlne Taken Before Meals

in a doubleblind subject-crossover study, he present study was undertaken_ as part or a phenyipropanolamine (propadrine, PPA) series of studies to investigate the effectiveness Of taken as sold over the counter reduced body phenylkopanolarnine inappetite suppression weight in 70 adults significantly more than a and weight control. This drug, also_known es nor, placebo pill. During the first two weeks, both ephedrine,is an amphetamine analogue that the subjects taking the placebo and those tak- causes little or no psychomotor stimulation.) It ing phenylprepanolamiae boat weight, but dur- bas the seine structure as amphetamine but with ing the second Iwo weeks only those uakhlg the an hydroxyl group on the beta carbon atom which drug continued to lose (p<0.01). On daily Ames- makes it more like norepinephrine. It is a vaso. donnairea, those taking the drug reported no constrictor and is marketed in most nasal decon change in the way they felt or the time it took geatants.2 Handbooks which aid doctors in choos to fall asleep. They did report a significant ing drugs point out that even though this drug is reduction in supper size and in the total num- commonly sold as an anorectic, there has been no ber of snacks taken. When subjects took the convincing evidence thit it_itt effective 3 4 There placebo, they reported significantly greater have been no well-controlled studies although number of large afternoon and evening snacks several ease studies indicate some effect. The than when taking phenylpropanolamine. It is reader is referred to Silverman' for a review of concluded that this drug, which isistructurallY phenylpropanolamine and to Hoebel' for a review similar to catecholamines and amphetamine, of the pharmacology of feeding. can cause w perceived decrease in food intake Studies with animals demonstratsd that this and reduce body weight without noticeable drug is much less stimulating than amphetamine. stimulatory side effects. In comparison it did not increase oxygen_ con- sumptiOni and did not appear to increase activity level Is much_as amphetamine even though it et From the department of psychology, Princeton University. festively suppressed appetite in rats as shown by Epsteint and unpublished work in our laboratory. 'From the Modica! Center at Princeton. It dyes, however, increase activity level in atabilt. Thiewtorkwowalrformid undeLthe_Millft[Oet of tne Brain Re. meter ceps. Daily injections of the drug reduced search Instruments Co.. 201 Medley Ave., Pronceton-, feeding and chronically reduced body weight ac. with_ wpm: titan the_ Allegheny PttanalIC at Colo not Pane.- cording to our unpublished dits. We found It ton University nor the Medical Center at "rinceton. ApOZecia selectively inhibited feeding, but not drinking, Ilion is expressed -to- TheOdore_acilthelliar_Relp_m_the gOn_lind design of this study. to Tom Transits° for help ,n the elicited by -electrical stimulation of the hno, experimental design and analysie_to_Marie_1wre_Karniin_and thalamus,* Moreover, it depressed hypothalamic Hetet c_e_Bonner for supervisory nett). and to Elyria Wilson self-stimulation wh amphetamine had the for compute, programming. and to Patrice Randall for help opposite _effect.* Thus, animal studies suggested with the data analysis this drug is an effective appetite suppressant Address for reprintt Bartley G Hoebel,_Dept__otPsycnology. without disruptive psychomotor stimulation The Princeton University. Princeton, New Jersey caw next question was whether or not phenylpro. Obesity/Baristric Med. Vol. 4. No 5. 1975

it" j11 'raj.ZU3 10

r . 203 199

panolamine_ would also_supp_ress food_intake_ in humans leading to weight loss without noticeable Tibia I Dlatdbulion of_Sublecte by Age, Sex and Weight Range (1070) psychomotor stimulation. Previous studies carried out by this laboratory with volunteer human subjects who were -con. 911.904ro. Web* cerned with their weight showed that phenylpro. paid& PlietWIWO- panolamine taken 30 minutes_ before lunch in a mem penal- einkie Tell double-blind study reduced lunch aize_.10 This Acs_ suggested that taken before every meal the_drug 9 would_cause weight loss. A_pilot study with 30 16-20 volunteers indicated that when taken as direct. 21$0 14 16 30 5 5 10 edonthecommercialpackage,phenylpro- 31.40 panolamine caused a significant weight loss not 41-50 13 matched in subjects taking a placebo similar in 5145 2 appearancebutcontaining noactiveingre, N.70 dients.II Weight Hinge The current experiment was designed as a Underweight 0 2 2 larger scale study of the effect Of phenylpro, Within desirable panolamine on weight loss in a double-blind weight rang* 6 2 crossover_experiment with seventy subjects" each .1-15_poundt serving_as his or her own control. We found that overweight 10 IS 25 phenylpropanolamine can cause a statistically 15.145 pounds significant weight loss. Overweight 15 25.1-poundsover. weight and above 10 10 --20 Method N.70 Subjects. Subjects were volunteers from the lex Princeton area who answered an advertisement Mile a 12 20 for people interested in their weight, Each pro. Female 25 24 90 spective subject was told that this will a medically N.70 supervised, scientific study involving an over the counter,- nonprescriptionappetite _s_uppressani and a placebo. It was_explainesLthat_they would receive each pill half the time_, but that they their desirable _range; The ages of_the_ gubjetts would_not be told when they were given one or ranged from 18 to 64; the initial weights from 113 to 261 pounds t_he other. They_ were further told that each person Procedure. Each subject received phenylpro. who completed the study would receive $20.00 panolamine hydrochloride during the two weeks and a month's supply of pills if they wanted it it of ...e study and the placebo for two weeks. The the end of the study. Following an examination subjects were randomly assigned to either the by the physician for evidetiee of heart edridition; high blood-pressure, thyroid disease; diabetes Or drug.placebo order of -testing- (two weeliS Of other conditions for which use of phenylpro. phenylpropanolamine- followed by two weeks of placebo) or the placebmdrug order (placebo fol. panolamine might possibly be contraindicated_; each volunteer wa_s_given a blood test ISMA CBS lowed by the drug). The_was_ order, counter, balanced_ so thatabout half the subjects had the DLF_F; T4-_ by_ radioassay) which was analyzed by the laboratory of_ the Medical Center at dr_u_g first-and the other half had _placebo first. Princeton. Seventy persons, 50 females and 20 The assignments were accomplished in two stem The principal investigator assigned subject num. males, were accepted by the physician and subse. bers to conditions, and the technicians assigned quently completed the study. -Adescription bf -the study population by age and weight is found in the numbers to the subjects in the order in Table 1. The weight tinge information for each which they appeared on_the first day Of the stud}: subject was determined_ with the use of the Desir- The technicians did not know which subjects were able Weight Range table found in the Statistical assigned to _which condition or even how many Bulletin of the Metropolitan Life Insurance Com conditions there were: The__subjects knew_ only their assigned numbers and that by the end of the pany; Volume 40; NovemberDecember, 1659. As can be seen in Table 1, two subjects fell below study they would have taken each pill_ half the their desirable weight range according to the time.No specialdietswereprescribedor Metropolitan table and eight fell within their desirable range. All other subjects were above HungrvA, alleeham Pharrnacal Corp: Ones!), ,Bariatric Med Vol4. No5. 1975

item Pane DW 017

204 200

what was eaten at each meal, thetime each pill suggested.- The - subjects were requested_toarrive perception of the size of weekday for_four weeks at h'.11 taken, the subjects' at the study aria each bi the meal relative to theirtypical meal size and approximately the__ same time of day to- the occurrence of snacks and theirsize. The weighed by one_ of three techniciansand to provide in of which was to Wand questionnaire was detighed to recive I vial_of three pills, one Experienced Meal. formation on physical symptoms be_tilien_a_ half hour before each- each day and sleep -patterrit. _ Pills were provided by the manufacturerin_the _ On the final day of the Study nurnerouswino- formers sold over the counter (25 mg)eXceptAkt taken of each sub. phenylpropanolamine. wnorphic measurements were the placebos contained no jest for funire reference; and afinal weight was Clear gelatin_cepsoles so the super. All pills were plated or recorded; The _principal investigator or there would be 00 differerice_in smalltime° how much weight he placed the cap- visor ititornied_engh_subject taste. The Principal invmnigator or she had lost orgained with the placebo -and sulescontaining_ eitherphenylpropanolamine with thefts without revealing thepattern of pill pills -or placebo_pills intovials, three per vial, $20.00 and subjects' numbers distribution, The subjects were given Whith were labeled with the if they wished, a month's supplyof the drug. and the_dey_the capsules wereto be taken. The technicians were responsiblefor lasing ths_t_ each Results subject was given the properVial each_ day. On for _subjects_ were The mesh body weights_for each_weighing weekends or other wig holidays all subjects ire Shown graphically in Figure 1.it given two or thfea datedvials of _capsules, enough first two.week appointment at the labors. is evident from Figure 1 that in the to last until their next period (left half of the figure) both thesubjects those taking tory. fill out two taking pbenylpropanolamme and All Subjects were also requested to the placebo lost weight, but those takingthe drug questionnaires daily, the first ofwhich described

ITO

169

1611

I6T PHE6YLPROPANOLAMINE PLACE90 A- 166

(65

9 10 1-1111 11-M19- I 2 3 4 5 6 7 6 164 -Th 11 9 10 1 3 4 5 6 T _99E- 2 WEIGHT WEIGHT WEIGHING WEIGHING Mel takIng_theplitibo_f_irat los] weight during Figura 1: SubjectsfttiplItiellakIngplienylpro- bOth_eitrtoes, Vetoes are given for the tan panotaMiiiiltrir Iwo weeks followed byplacebo the -drug and waighings In each two -week period (IA; no WARD weeks lost weight with- weighing. on weikeride): gained weight with placabi: Subjects(bottom . obesityfEtatiaitic Med Vol 4. No 5.19-5

mot Palmgal Oce

205 201

Table 11: Mean Body Weight at the Beginning (MN Weight) NW at the End (Tenth-Weight) of Each Two Week_Test_Pirktd. EaCh SUbJect_ToOk Phinylpropanallonanalitifine Meals PeriOstArtd_e_PJacibo for the Other Period. Net Change In Body Weight and Pesosnt of Body Weight Loss Are Also Shown.

Group

1st 2 wk.. -1...106.78 164.77 -2.01 -12 , 6434- 164.71 fro2 Placsbo- 2nd 2 wits. N -34 ' a444f1.42

1tt 2 wks. 169.74 108.61 -123 ,-0.7;:1. 2602.7 106157 0

' 2nd 2 wits.1!.8117;f. . . . :" -4.,:vc.t;n7-14 .

N.7'11.- . *. appear to have lost_ more weight: In the second phenylpropanolamine during That periodlost two-week period, shown on the right side of more (phenylpropanolamine; 1.2% weight loss vs. Figure Only those _people who took the drug show a loss in weight. Weight on the da_y when subjects were switched from one condition to the PLACEBO-DRUG DRUG-PLACEBO other (midweight) is not included in the calcula- CONDITION 1. CONDITION tions. Table II summarizes the mean weight of subjects at the beginning and end of-each two-week E test. People taking-the drug the first two weekS List an average of 2:01 pounds, then gained back 0 Sr 0:16 pounds on placebo: The other group of peo! : pie who had placebo first; lost 123 pounds and '&7 2 then 105L1,411 pounds with the drug. Combining 0.6 the two_grou_ps without regard forwi.h.hpill came :0.4 first, the 70 subjects lost 1.7 pounds with the drug an and0.54pounds with the placebo. This is shown 0.2 in Figure 2 as a mean percent weight change. 0 An analysis of variance was performed on the x 0 percentages of weight.- lost during each drug ad- ministrution_ period. That is, for each subject we a'0.2 calculated the percent loss (or gain) relative to the initial weighing of_tbat_drug administration 0.4 period. In the first period the t .40. weight (day 10) -weight (day I). r. 0.6 % weight ehinge weight (day I) Likewise, in the second period, '"g weight (day 2k) :.weight (day 12). % weight change weight (day 12) Thg_pe7c_entbody weight change for both groups . appears in Table II. The anablis of variance in .7-14, 'Cf Table III shows that the percent weight loss at- 7::11 - --.'e"- tributable to phenylpropanolamine is statistically FlCure_.t_ Pereint_svelpht_theepe Atom_ the reliable IF - 12.75, p<0.001), but that the loss due starting weight showing that phernOpropanola to this drug was different far -the two groups mine and placebo an both associated -with depending on which pill they-had first. This find- weight loss the first two weeks, but the drug, ing was contirmed_by a significant drug by group Indatertwelpht SteateL(101 hand bar In interaction iF8.90, p<0.011 each palrLend only the drug caused weight __Within _thefirst two-week tune period, both loss the second two weeks (right hand bar In groups lost weight although the group taking each pair). Obesityl3anatric Med Vol. 4, No 5. 1975

_Tht_.Poe I 9 202

' - the time they wire receiving the placebo. Figure 3 Thb WEE lySli Of Visional of Moan Percent shows the overall effect_of_phenylpro_pa_nolamine Weight Loam placebo in terms -of per cent weight _loss, whereas Figure 2 depicts the effectiveness of Smartie et Vertitleir' ` Fl Sloan lkfue F p_henylpropanolamine in producing weight loss for each order of drug administration. When sex (DrogRiscebe ss 2 was added to the previous analysis -as another Placebo-Drug): A .1.-47,4*.itit2i0 -20/5 variable, there were no significant differences in Error ;1/.4 itfi0A 10 -2 weight loss between-men and women. P R - 204 A10 -2 1215 Summarizing this body,weight_data, it_is clear A tit a 4,142 A10 -2 11.90 that the placebo hid _a strong_effectin_the first Close Error ." Diexte-t two _weekphaseOf theexperiment. examination of Figure 1 shows that there was even a decrease in weight between the time the subjects were first weighed during the doctor's examination (preweight) and the first -day pills were administered a few days later. Thus- the placebo 0.7%), Post hoc comparisons (Sheffe subjects' anticipation contributed to weight 100S: method) of these mean losses indicated that the both a placebo effect and the drug caused difference was not statistically reliable (F (1.68) weightloss during_ the first two weeks of _the w 2.71, p>.05). However this' comparison between study, but only_the drug caused a w_eightloss dur, the mean percent weight less of the two groups ing the second two weeks and this effect was during the second two.week period tphenylpro. significant._ _ panolamine 0.9% weight !oat vs._ placebo 0.2% The_subjective drits_on ease of getting to sleep weight gain) was significant (F (1.68) 13.10, and energy levels were analyzed by a matched ri.C.J35). pairs test of 35 subjects who reported -at least Over the entire month of study, a greater total once that it took more time than usual to rill loss occurred for the placebo.drug group (overall asleep the previous night. The -mean number of 2.63 pounds, a 1.6% loss) because the other-group, such- responses -while_ taking phettylpro drug-placebo. (overall1.85 pounds. 1,0%_ loss) panolamine-was 1.71 and while taking _the_Pis actually gained a small amount of weight during cebo, 2.09. The mean difference_was_not found to be Significant. The_corresponding means for the 35 subjects who recorded at least once that it took less time_than_usual to_fallJeep at night were 2.14 for the drug and 2.43 i'dr the placebo-The +0.6 meandifferencewas notsignificant. Thus phenylpropanolamine did not affect perceiVed froi4. 0.4 ease of falling-asleep. + 0.2 Similar results were found in the analysis_ of energy-level data. Th_e_rnean number of reports IO7 for these 33_subjects reporting at least once that they had less energy than usual in the last 24 6"0 2 hours was 2.61 for phenylpropanc:smin: and 2.61 for the placebo, i.e. no difference at all. For the 32 till! subjects reporting more energy in the-previous 24 ww-er -0.6 hours the mean number of Buell daily responses - for the drug was-1.69, for the placebo I.50. again k_! not significant. These results show that -this drug did not affect sleeping_hahtts or energy levels am ---- 1.0 P<0.001 'differently than did the _placebo, On the question which asked if subjects noticed - 12 any unusual tastes or feeling, there were so few - 1.4 responses of any kind that an analysis was not attempted. The subjects' personal records of meals. snack4 Figures 3: The tarribitsed mean _percent weight and whether-they ate less, the same. or more than 10iii_forell 70 subjects when taking phanylpro Usual at each meal proved very interesting Each winolernine significantly exceeded weight loss Of the significant results in _Table IV was in the when taking the glidtb& direction one would expect for an effective appe Coesity/Sanatric Med. Vol4. No5. 1975

. - "Mei ID.11.456F1

207 203

Table IV: Moan Number of "Lass than Usual" and "More than Usual" Responses for Meals and Snacks, and Total Number of Snacks

Main Mean Level Responses -Responses Veen -of N ler Drug for Placebo Difference t Stunt!.

Pended "Ms lets than minor: Breakfast 49 4.06 4.12 -.04 -tilt NS_ AM snack to ss 3.51 222 .69 121 NS Lunen 80 1.10 3.73 37 1.23 NS PM smack 46 3.67 3.17 30 1.15 NS Supper `,-"' 59 3.71 2.71 120 228 205 Evening smack 49 3.45 220 .55 113 NS Total masts "-cr. and snacks 70 16.49 14.00 2.49 2.88 .01 . Responded "Ala more than maser': Breakfast 56 1.50 1.T -27 -0.97 NS AM snack 29 1.66 1.66 20 20 NS Lunch 51 2.02 2.43 -.41 129 NS PM snack 47 1.47 1.98 -31 2.11 .025 Supper 57 225 2.60 -35 1.54 NS Evening snack 59 211 2.77 -.46 1.66 OS Toll meats end snacks 70 8.09 9.67 - 156 2.59 21

Total number of snacks regardless of sire: 66 14.93 16.31' -1.38 - 1.99 OS Statistically significant tite suppressant. For example, there were signif. which causes_ weight loss_by surbing_ foo_d_ melte icantly more responses of "ate less than usual" without notable side effects might be a valuable for supper for people on th_e_drugthan on placebo. medication for some overweight people. Conversely in the "ate more than usual" cate- The side effects of this drug seem to be minimal gory, afternoon and evening snacks were indi to the extent one can judge from the subjective cated more often by people on placebo than peo reports we collected daily. The drug is maketed pie on the drug. Also revealing is the total num. widely as a nasal decongestant,-and it can affect ber of snacks reported. Subjects-taking the drug blood pressure although this effect is relatively reported a mean of 14.9 snacks. When-taking pla minor,) Now that _we have demonstrated a cebo they reported 16.3 snacks (t.- 1.99, p<6.05). behavioral effect in the form of decreased food in. Thus, judging by the subjects' own reports of food takels with a loss orbody weight as shown here, intake; we would conclude that the reason_ they one wonders if anyother behavior systems are a lost more weight with the drug than with placebo fected, At the present time there seem to be no we, because they ate less, particularly at supper, studies looking for any influence on thirst, sex or and they cut down on the size and frequency of other basic behavior patterns in humans. Several afternoon and evening snacks. studies report no evidence -that the drug is a stimulant at the dose tested,5 -- Discussion If subjects- -can detect side effects, thereis Insurance company statistics have shown that always a possibility in human experiments of this people live linger if they keep their weight down type that they give results due to their expects. to the young adult leve1,12 and some medical ex- tions_ which they_then laheLas_side_e_ffects, The perts rnaintain_s hat even _a_trahstent weight loss effectwe observedforphenvlpropanolamine to give the heart a rest can be beneficial as noted would seem to be reasonably specific because at the Ciba-Geigy Conference on Obesity: The there was no effect on the subjective reports of Human Energy Crisis, 1973. Therefore, a drug feelings or energy level even though there was a 011eSity/BariatriC Med. Vol. 4. NO. 5. 1975 0'01021

t 204

weight loss. Similarly, in our studies of lunch size, day than the first and this was not true for people the subjects ate less on drug days but generally who started on the placebo. The overall results did not report feeling any different when they show that phenylpropanolamine (25_mg) can on filled out-the questionnaires immediately after the average cause at least some weight loss and the meal. Therefore, we assume that the subjects' this, _of course, means that some individuals expectations were properly accounted for _byt the might lose many_pounds and others not at all. placebo control procedures and within-subject Divert our positive results and the fact that most comparisons _built into this study. people by far do not find this drug to be a stimu _ Oneshould also be aware that our evidence for lent, it is reasonable to suggest that this is a drug a statistically significant weight loss in a two- of choice in a doctor's search for an appetite sup- week period does not mean that this rate of loss pressant that is medically useful for some over- would be continued over longer periods. Drug weight patients. tolerance and a nwriad of other physiological and In conclusion, this study repeats on a larger social factors could affect longer term results. scale the basic _finding of our prior study and Both the pilot study and the present study dentonstrates_conclusivelythatphenylpro- 'bowed a statistically significant weight loss with panolamine can cause a statistically significant ,heny/propsnolamine. Statistical significance weight loss in people who take itas directed does not necessarily imply_medical significance; on thepackage.Specifically, we foundthe doctors can _judge whether or not the average following: 1) The 70 subjects in this experiment weight losses reported here are worthwhile. In lost weight significantly over a two-week period our two-week pit( t study with 30 subjects, 15 on when they took phenylpropanolamine - compared phenylpropanolamine and 15 on placebo, the to a placebo; 21 they reported no feelings of phenylpropanolamine subjects lost weight. 3.8 altered miergy level and found falling_asleep_no pounds, and the plierbo-subjectsilid not. In the more or less_ easy thsn_usual; 3) their food intake present study with 70 Subjects, all Of whom had was significantly affected according to their own both phinylpropanolamine and placebo tests_the reports. When taking phenylpropanolamine the subjects lost about one pound-in anticipation of subjects reported eating smaller suppers and few the study, another_ one or two pounds in the first er snacks. two weeks depending on whether they had the These data therefore demonstrate that phenyl, placebo or the drug, and a third pound in the propanolamine was effectiveinproducinga second two weeks if they had the drug. There was awn-term weight loss in the population sampled. an indication that the drug started working the They further suggest that weight loss was &CUM- first day: the mean weight for people who started plished, at least in part, by a decrease in food tn. taking the drug was significantly lower the second take.

REFERENCES .

1. Innis_illautallackerson 1,11-Doigs sating on rvingtar4lionic phonnocolooy. New York, Plenum Publishing Corpin edrsnergic nerve endings sod mutton untwisted by _ pow). tf*M_OrrilpIthOTIIIWIC drugs). In Goodman LS and Oil. 7. Minter SAL: ActIoni of betwedrimo and propedrins In the wan A-(eds) PhillfileCObRICILIMINt of Terspoutles, ed 11. PlaLtnil obooltINutt arjO. 1944. New York OlacAtOlon Co. 1565, do MAN S. Epatelo-&-Supproeslon of APO% and ddradoglay-arsolle Welan AL Skillads of entivbsta/fif drugs. Springfield. Owning and other Mugs In normal and hypsrphegIc rani J HI,- CC- Thomas 24.1162 - , - CompfiftysloLftishol3231, 12611 AMA Council on (up AMA Drug Evaluation 1171,Oil.... 1. Huber 110,-Peedlog: Newel-control ofPULL Ann -non Ohlulgo-Arroduri_Usdical ISI1. :I. It7WOr 1$71, r 1 - Modell W end Ruder 0/3 0141-01COOko finfen. Woobl-K at-el-pOWtieuporaaloor b Wessbo 1115.- 'nuts. Mae rt Co-lira, M111413. . ' penolamine lo humus Obsellyilertst MW 4Aft2 Saurineol41 Pfitinyloropanolanfinesherd) or 'Imply 11.140,391 IIKIIIII100000NI; Teo 01W ofpropAd rine on food O wed? Amor J Poor, 136 46, 1553. - IntnAoin human. Aspen lo Allegheny Punnacal Corp., Hubei DO PhanstecolOgy Of Wilding In tunas LL, tvw 1172. e on SO and Snyder Sri (Ws) 1111MI000M of Porch* 12. Soclery of Actuaries Transactions No 1,1260 205 MS. OAKAR. Thank you very much. Dr. SILVERMAN, Thank you, Professor Coons. Now,if we could have the committee's indulgence andeven though they have no preprepared statements; I would like to ask if it wouldbe appropriate, and I would gladly give upmy seat if the three consumers could come to the front and present theirown testimony. Ms. DAKAR. What I would like to do first is have thecommittee ask questions first and then have the witnesses, and we'llask questions. Dr. SILVERMAN. Of course. MS. OAKAR. Mr. Lantos? Mr. LAiwros. Thank you, Madam Chairman. Dr. Winick, I was very much impressed byyour testimony, and there is just one item I'd like to explore withyou Did I hear you corre:tly tilat 101 substanceswere more frequent in their appear= nce? WINICK. Yes; sir; that's correct. Mr. LANTOS. Could you expandon that study a bit, because I find it startling? Dr. WINICK. The Drug Abuse Warning Network,Mr. Laht6S, is the country's most broad-based and representativeprogram to col= lect information on overdoses, accidents with drugs,and so forth: It's unlike the poison control report; whichwas a one;shot and coy= ered a finite period of time Theemergency rooms that -report to DAWN; which is an agency jointly_ sponsored bythe DEA and NIDA, do so on a regular basis. They report allemergencies. that come to them. And the results are analyzed on a quarterly basis and they have been published now for 10years.. -In_ the most recent one, which covers the third quarter of 1982, o£ themany substances listed; 101 were more frequently cited than PPA, andPPA accounted for .017, less than one-fifth of 1 percentof all of those Men= tioned. Mr. LANTOS. I hope my next question is-notan unfair one HOW many of the 101 substances which appeared more frequently have been ruled off the market? Dr. WINICK. Well; some of them; ofcourse, are illegal substances, such as heroin. Tbey're not available at all Mr: LANTOS. Yes. Dr. WINICK. So that includesmany substances which either are illegal or, like cocaine, whichmay have an accepted medical use but which are used for mood modification inan illegal Manner. Mr. LOrroS Are there any of the 101 which appearedmore frequently which are not illegal that have been taken off themarket? Dr. Wilvicx. No, not to my knowledge; Mr. LANT08. SO what you are suggesting is that substanceswhich appear more frequently in the DAWN study arenn the Market? Wirncx. Very much so; yes. Mr. LANTOS. Very much on the market. Could you giveus examples, any of you gentlemen; of these substances,any of these stances? Dr; WINICK. No: Mr. LANTos, For a layman it's fascinating to observe whythe on slaught on PPA when apparently there are dramaticallymore dangerous substances; and many of them, which are freely being bold.

27-436 0 - 84 - 14 210 206 Dr_ WINICK, Well, for example, there are manybarbiturates on the caffeine, for example, is number 90 in termsof mentions. Aspirin is number 50. In other words, there are anumber of widely-used substances that are much morefrequently cited than PPA. Mr. LANTOS. I have a question, if I may,Madam Chairman, to Dr: Coons. As I take it your testimonyis that rats don't read the newspapers and do not watchtelevision; therefore, are not influ: enced by the manipulation of theadvertising agencieS. Dr. COONS. Well, they're innocent of mediainfluence, I trust: Mr. LANTOS. You think they're innocent of mediainfluence? Assuming that that is correct, could you expand onthat study? Because I find that a great deal of tht :-.Arliertestimony focused_ on deceptive advertising, and that is why peopletake these, and that is why we have such a problem. Dr. COONS. Well; de have a phenomena thatis known as the placebo effect. It's oftenit often has very good properties;that is, it's a pSychological effect: A personthinks they're getting a drug and they aren't;_ they're getting a sugarpill, but they go ahead and do very well Then, however,there are people who think they're getting a drug who have some otherpsychological reaction to the drug, which is really a sugar pill, and havebad effect. So, what you have to do to get aroundthat is to test in animals and, as I said before, they're innocent ofthese kinds of influences, of preconceptions of what a drug mightdo for them or fears they might harbor about a drug. Thus, you can look atthe outcome of a drug treatment in animals, with appropriatecontrols, as bearing a great deal of weight in telling whatthe true effect of the drug is; over and above the placeboeffect or, in other words; the powers of suggestion. Mr. LANTOS. I have ,)ne final question, ifI may, Madam Chair- man: It's not unusual _for professionals in variousdisciPlineS, even economists, to disagree. And we haveheard physitians who have taken a point of view different from what wehave _heard iately. I would like to get a general statementfrom each Of You if I may, whether on balance itis your view thatthe products we are discussing here are harmful or helpful to theAmerican public. Dr. SILVERMAN. Well, let me start off andlet me say as firmly And as convincingly_as I can that theproducts that we are discussing; that is, the OTC products ingeneraland phenylpropanola- thine Specificallyare safe, they'reefficacious, and in my opinion SS a professor of pharmacy; forupward of 30 years, there's no question but_what the American publicis receiving are safe and effiea- cious OTC medicines, very helpfulmedicines. In point of fact; and something that WASnot yet mentioned during today's review and hearing, isthat not just one; not just two, but actually three FDAreview panels have reviewed phenyl- propanolainine specifically from thestandpoint of safety, beginning with the cough and cold panel, whosemonograph was published in 1976; the weight control monograph,which was publiShed in 1982; and a monograph also publishedin 1982, which always seems to get lost in the cracks, butwhich reports on the and use of phenyl-

.1 f; 211 207 propanolamine in the oral cavity, finding phenylpropanolamine to be safe. Three separate expert panels found phenylpropanolamine to be safe, three independent expert panels working at different periods of time over a period of approximately 7 years, with the latest monograph published only in May 1982: PPA is a very safe and a very efficacious drug Of this I am absolutely convinced. Dr. COONS. Well; human research is not -my specialty- so I would, again, address riyself to the rats and say that I think that PPA, in the--- Ms. OAKAR. There is a similarity? Dr. COONS. Yes. In the doses that I've administered in my study, which went- from half the normal dose up to 20 times the normal dose equivalent for humans, was safe. These were in normal ten, sive rats, not the rate that are h_ypertensive-prone, as you heard from Dr. Mueller, So; that's my contribution. UNIDENTIFIED VOICE. Several years ago, just about 25 years ago, I was an anesthesiologist and I have learned, I believed, quite a bit about medicine becausewas dealing with life and death every day. I left anesthesiology voluntarily because my first love was to treat obese- individuals, and they always remind me of that song, you know, laughing on the outside and crying on the inside, and I have done everything in my power to try to help thee?. people and they do need help, The amphetamines were taken off the market because of abuse. They were excellent appetite depressants. Search has continued since then, and involvednvolved with the research work for finding a way that we could help these people, keeping in mind that obesity, it's a complex medical disease; and that you need to treat not just with medications. I was very happy to contribute to the research work on phenylpropanolamine because I found that it is an adjunct; a very valuable adjunct, in my practice. This morning we were talking about blood pressure, and so on There are still many doctors that will not give a medication to a patient who happens to be obese and has high blood pressure, and yet there are people that need these medications; and I have found that blood pressure actually comes down because of the improved health. That's the benefit that you get by losing the weight. But again, you treat the individual who happens to have the disease, and not just the disease. And this is why I hope that I will be given the privilege to continue to use phenyipropanolamine; along with other modalities, in my practice, and I hope that that day will never come when I will have to give that up. Thank you. Dr. BRADLEY. As stated by Dr. Conte, and we've heard a great deal of testimony today that the obese hypertensive is at great risk with this drug, on the exact opposite side I would say the obese hypertensive is in most need of losing weight, because as a person loses weight his blood pressure tends to normalize, In my study, I entered into this study because I felt a great need for this type of medicine and to date I have seen no side effects, I have seen no aggravation of hypertension. I think this is a very important tning. I am very much in favor of this medicine.

0In 208 Dr. SILVERMAN. Before Dr. Winick continues,may I just -comments so_that it is or( perlyhighlighted, on the study of Dr. Brad- ley, Dr. Bradley deliberately usedhypertensives and_it's-continu- ously said that only healthy people are everevaluated, when PPA is tested. Now th:s study wagspecifically done to evaluate just What is the effect of PPA on thegeneral population. Dr. Win ick? Dr. Wii;acx. I would like to saythat having looked at the literature on the effectiveness ofPPA in weight reduction, there is no doubt in my mind, first of all, that theaccepted criteria for conducting such studies have been followed.There is a standard -way of doing medical research with acomparison group and using accepted, conventional statistical procedures. Every one of these studies involve the useof exactly the kind of methodology that would be taught in aclass on the conduct of social or medical research, and the dataaccumulated, it seems to me, are quite overwhelmingin terms Of demonstro ing, certainly, effectiveness and aarety. In terms of the other side of thecoin, the haiarda that have been alluded to; my studies of epidemiologywhich have been conducted by and for agencies of the FederalGovernment, foundationS, State agencies, and concerned citizens,certainly haVe led me to conclude that there is no hazard of abuse here__,this is not a gateway drug, it doesn't lead to other drugs, otherdrugs don't lead to it, and _so fbrth, and it seems to me thatevaluating the very clear and consistent _demonstration of effectivenesswhich involve the application of eatabiiahed procedures andevaluating the nonexistent risk of abuse that the situation is a clear one. In terms of the nonpublication inthe journal, let me just say that the International Journal of ObesityIS one of the world's leading journals in the field. It's relatively newand perhaps that's why it's not as well known to some persons asit might be. It is a refereed journal with peer review and it'sedited by a very distinguished scholar in California, a medicalscientist connected with a medical school with an internationallydistinguished board of advisory edi- tors. It perhaps might be well just tomake that explicit. NOBLE. Ms. Oakar, gentlemenof the panel, in the next 1 Minute-60 secondslet me summarizefor you my 15 years experience in treatingoverweight patients, first as codirectorof the Obe- sity Clinic of the University ofCalifornia, and subsequently as director of my own private clinic inSan Francisco. First of all, I think I've Seen about 10,000 patients, andwith the exception -of Dr. COnte, I don't think anyone has seenas many patients as perhaps he -and I have. I think he's seen about10,000, too; So, I think we are in a position totalk about real experience: These are people who come to uswanting to lose weight; We're not talking about rats or what one hasread in some Australian or fa ra wayjou rn al . First point, of these 10,000 patients,I can count only on 1 hand maybe 2patients over age 70:So; I would say to you, don't worry about the elderly rushing outand :getting diet pills: For some reason, they're happythey're 70 and they want to stay Wherethey are and they don't want tolose weight in general. Ms: DAKAR. What about people who are over50 or 60?

213 209 Dr. NOBLE. Yes, definitely more in these groups. Ms. OAKAR. You have to be worried about -them. Dr. NOBI.E. Yes, but I'd gay 70, very feW. Thereare some who are 50 -and some who are 60; The numberseems to go down after that. Now, with respect to the efficacy of phenylpropanolamine. Mr: LANTOS. Couldn't you find an edgier nameso we can all pronounce it? Dr. NOBLE. I'm sorry. PPA. You know; it would be really __great if, as a doctar,a patient comes tc me seeking to lose weight if I could merely say, "get out there and try willpower and lust cut -downyour calories:" That Would be marvelous. But you haveno idea how many patients have tried thisathousand times before. They come to- the doctor and they want him to givethem something. All right? So what do I give him? I haveto give him some= thing. I find that phenylpropanolamine is justas good us anything by prescription.. So why not give them _phenylpropariblainineand save them all the problems and cost; specially if there areno side effects? The second Point: How safe is phenylpropanolamine? I thinkper haps I've studied phenylpropanolaminemore than -any other person in this country at the clinical level. I would say I haveseen and tested now, in double-blind, well- controlled- studies about1000 patients. These are very restrictive studies andwe have to report them to an institutional review board. We have to be totally I have tested under these conditions abouta thousand patients,1 would say 600 on obesity and 400 on Cough/coldprepara- tions. I have yet to find one side effect that really shookme up, with one exception. Let me tell you about this. In that 216=patiorit studythat I just talked to you about, Which wasa 12-hour study._rm addressing this to_ some of these people who, quote-unquote, "Were victimized by PPA." Patients in this 12-hour study could have receivedas much as 75 milligrams of PPA. Everything_ went fine. HoWeVer,one patient went home and at 4 o'clock the next day she calledme saying, "Oh, my God, Doctor, I've gOt severe CheSt pains, my whole left side is paralyzed; I'm short of breath, I've got this ringing noise inmy ears, I can't even hear you on the telephone; I've gota headache, get over here." I said, "Oh, my Lord; what have I done now? Did PPA do this ?" I rush over there. She was Sort of a beatnik living in sort of beatnik conditions. She looked fine to me but she. said, "Doctor, I See but- terflies jumping _up and down across the dresser; Don'tyou see them?" I said,`No, I don't see them." I examined her and found her physical state to be normal; I went back and under emergency conditions I broke the code-to see what she had been getting on the studs the pi-OA-di:1S day. Lo and behold, she was getting placebo; a dummy pilL Now;are we going to ban placebos because they cause hallucinations, chest pains, and all these weird things that this patient was complaining about? All I'm saying is that when you are dealing with a product that's as common as PPA; there are going to be various reports of oddball 214

E. 210 things happening, and it would be unfair toblame it all on PPA because if you delve and probe; Idaresay with most of these victims today you might well find alternative causes. Thank you very much. Dr. SILVERMAN. We might addthat a placebo is a sugar pill, an inert pill. It has no activity whatsoever. Ms. DAKAR. And you're saying thatall of you, in your testing, use placebos and the patientsdid not know that they were getting placebos? Dr. NOBLE. Absolutely. MS. OAKAR. Are you going to saythat for the record? study. Dr.Fuimisiitsuilfc. That's called a double blind Mg. DAKAR. Right. Every single oneof you is going to say that? Will you say it, from Johns Hopkins? look at BRADLEY._It's all controlled; it's all coded, we caancit what is given; we have to be impartial,and at the end of the study then they finally tell us who got what. FUNDERI3URK. I can speak to that from astatistical point of view and an experimental designpoint of view. The way the studies that we conducted at Hopkinsand that Dr. Noble conducted And that all of us at this table haveconducted have been conducted under what are called double blindconditions. The drugs are packaged by an independent party inidentical capsules of identical shape and appearance. There is no wayin _which to tell which is the active drug product and whichis the placebo. The patients are administeredthe medication under identical conditions and all the experimentalprocedures are the same for all the patients in the Stuiiy. There is absolutely_no way for aninvestigator to know what the patients are getting. The data aresubmitted by the investigators to the sponsor _or whoever is going to dothe statistical analysis of the data and at that point, When thedata are in hand; the code is broken and thestatistical_analysis proceeds; Once the statistical analysis isCompleted, _then you have the completed report, which is then givenback to the investigator, the statistical report, for his clinicalevaluation of the results. And that's the way the studies have beendone. All the studies that are listed here were conducted usingappropriate scientific methodolo= gy and just to comment abit further on a point that Dr.Silverman made, there have been a largenumber of studies conducted under double blind conditions,well-controlled, clinical _evaluations of phenylpropanolamine; at re-Commendeddoses, and the evidence is just overwhelming in termsof the absence of side effects; andthe efficacyof the product Dr. SILVERMAN. Thank you,Mr._Funderburk. Dr; Sebok? Dr. Subic. Overweight people mostof the time, if they are not Sick, are overweight because theyeat too much. Most of them will not admit it. They don't evenrealize it So; if we give them PPA before meals and they unconsciouslylearn better eating habits and are not hungry andwill eat less,_ this will help themfor the future to keep up the good eatinghabits; We don't expect them to keepit up forever. The aim is to use PPA as a crutch to help them tolearn better eating habits. Ceic thinly, either the doctor orthe person himself has to realize;

215 211 whether he is a candidate to take PPA or not: Sick people should not take it. Ms: OAKAR. Thank you. Thank you very much. Dr. FUNDERBURK. Thank you, Madam Chairman. Dr. SILVERMAN. I realize it's late but could I ask the committee's indulgence for an afterthought by my good colleague, Dr. Coons? Ms. OAKAR. No; rrn sorry to say: My colleague has questions, I have questions, and we should have been out of theroom at 1 o'clock. We also want to hear from your other witnesses. So, let's proceed Mr. BilirakiS? Mr. BILIRAKIS. Thank you, Madam Chairman. Well; I came to this hearing principally because I was concerned with the misuse of the over-the-counter-type drugs by the elderly: And I'm still concerned with that. Obviously; I think that misuse of any drugs on the part ofany- body is of concern, and we should meritoriously be prepared to tackle those types of problems. But I haven't heard that much testimony in terms of the adverse effect on the elderly, which ismy biggest concern. I guess the entire hearing has evolved into-an attack onan onslaught, as Mr. Lantos very ably put iton PPA. If PPA is- dangerous; then so be it. We should be concerned about that too, because it's going to affect the elderly as well as the rest of the population. I would ask Dr: Bradley just very quickly, since hecomes from an area similar to mine; L am from the Tampa Bay a-ea; sir, with about 50 percent of my district being elderly. In the studies that you referred to, sir, about how many elderly were included in those patients? Dr. BRADLEY. Our protocol allows for up to 874. That's been approved by- the Research Committee of the Miami Heart Institute, and the Human Subjects Committee: Our oldest patient so far has been 70. We've had another of 67. I have an older population that I have to choose from. So, they have been in the forties, fifties, sixties, and seventies; one aged 70: Mr. BILIRAKIS. Dr. Winicic, would you have any opinion, sir, in terms 'if the percentage of p?,ople who take PPA, which are in the elderly category? Dr. WJ!:ICK. Well, everything that I know, sir, is that it's a relatively small proportion of the user population, and if you look at, say, the text of magazines like Modern Maturity or Fifty Plus; even though there is, of course, an enormous amount of material on health; and ion eating well, there's relatively little on diet pills or various medications to help oneself to eat less; and if we look at the data from DAWN and other sources, of difficulties that people have had, the senior citizen population is very, very small, consistently small. So, my sense is that; A; it's a relatively small proportion of the user population that involves seniors, and that they area therefore;- underrepresented; and if they take it, they are less likely to get into difficulties than younger persons, contrary to what has been said about them in general, in terms of these substances. [The following material was subsequently received from Dr. Win' ckd

f "1 216 212 This statement is submitted for the record of the House Select Committee on Aging, Subcommittee on Health and Long-Term _Care, to supplement my remarks at the July 21, -1983 Hearings on Drug Misuse and the Elderly, and in response to matters raised during the Hearings. I shall deal with the epidemiology of phenylpropanolamine (PPA) use as it invOlVes the older user.

EPIDEMIOLOGY OF PHENYLPROPANOLAMINE USE BY OLDER PERSONS All aVailable data from survey; marketing; observational and treatment sources indicate that senior citizens, defined as persons aged 60 or more; seldom takes appetitie suppressants. For most of the senior (60 +), or e.derly (65-75), or old (75+) 130P- ulation, the kinds of 'osmetic or asthetic appearance considerations-which may be important in earlierperiods_of the life cycle are far less salient. The = comments below summarize my observations, in a naturalistic market situation, on the phenYl= propanolamine purchasing behavior of a substantial sample of consumers; two dif= ferent analyses which I conducted of phenylpropanollimine consumer _response forma; and a summary of industry practice with respect to selling phenylpropanolamine pro-ducts to persons over 60. The studies of my own which are cited below were conducted for other purposes, but it has been possible to analyze the age data for purposes of this submissicn. The three studios which tre summarized below clearly indicate that the use -of pheny:propanolamine is _so minimal that it cannot be eligible to be coniidered health hazard to senior citizens. 1. Observations of consumers purchasing phenylpropanolamine producto:_During 1976 and 1977, I observed over one thousand persons shopping for appetite suppras- sants in discount stores, drug stores, and other retail establishments sellingthese products in the Metropolitan New York area. A sample of these consumers was then approached in order to make arrangement§ for a personal interview, to be conducted in their homes, at their convenience. My field notes of the total population observed (n =1,053) indicates that 11 percent were bet veen 50 and 59 years old, in terms of their estimated age. There werethree purchasers aged 60 or more, or 3 percent. Since these _observations were conducted over a period of many weeks, their validity would appear to be high. _I have used similar techniques of visual assessment of demographic characteristics of consumers in studies sponsored by the National Science Foundation and a Presidential Com- mission. [1) 2. Two different analyses of consumer response forma I have conducted two different analyses of reports of consumer experiences with phenylpropanolamine Prod- ucta. In 1975; I-studied a 100 percent sample- f the 3,245 package inserts submitted to Thompson Medical Company by purchasers of its appetite suppressants containing phenylpropanolamine in -1972 and 1983: [2] These inserts included information on hoW long the product had been used, the outcome of its use;and demographic information, including age. In 1977, I similarly analyzed all of the 422 insertS-received from phenylpropanolamine users during a five week period in April-May 1975. [3] For the 1972-73 sample, the average age of the consumers was 31.8 and .6- percent of the users were 60 or over. For_ the 1975 sample, the average age was 31.5 and .5 percent of the users aged 60 or over The -60 plus age group accounts forabout 12 percent of the population. So that with less than one percent a_ctually buyingthe product, senior citizens represent minimal users of phenylpropanolamine products. Put another way, Persons over 60 are extremely underrepresented amonr phenylpropanolamine users. 3. Industry practice with respect to selling phenylpropanolamine products in persons over 6a A content analysis of all the advertisements inthe two leading magazines for senior (Modern Maturity and 50-Plus) for the periOd 1978-81 found that there was not even one advertisement for appetite suppressants in these publica= tions. This study was conducted as part of a Th.a_thesis on media images of the aging. [41 The appetite suppressant industry clearly does not promote these products to senior citizens. Thompson Medical Company has, on all of its phenylpropanolamine appetite suppressants, the statement, inbold_face type, that the product should not be used by persons_"Under the age of 18 or over 60 except under the advice and supervision of a p h y s i c i a n."--- The industry is not advertising its products to senior citizens and Thompion Medi- cal Company actively discourages personaover_60 from buying them. Since the studies cited earlier indicate that senior citizens reprewnt _minimal users ofphenylpropanolamine appetite suppressants; and since the industry advises senior citizens not 213

to buy these products, there would seem to be a minimal publichealth hazard nosed by senior citizens' use of these products.

REFERENCES 1, C. Winick, Some Observations_ nCharacteristics of Patrons of Adult Theaters and Bookstores, in Volume IV, Technical Report ofthe CbmniiSSion on Obicenity and Pornogapby. Washington: Government PrintingOffice, 1971, 225=244. 2. C. Winick, Two Consumer Studies and-a Reporton Abuse Potential of Phenl- propanolamine. Submitted to the Food and Drug AdministrationJuly, 1977. 3. Ibid. 4. B:C. Iketterle, Media Images of the Aging. Ph.D. Thesis,Department of Sociolo- gy; City University of New York, 1983. Mr. BILIRAKIS. Olcourse, since theyare more HWY to misuse the drugs as a result of not being able to understandthe labels, or not bothering to read the labels; orany of the other problems that result from being elderly, or their eatinghabits being somewhat different. I'm certainly not belittling;Madam Chairman, the need for this type of a hearingas it involves our elderly; Ms. DAKAR: Right: Mr. BILIRAKIS. I'm just trying to getto the proper perspective in terms of percentages. Ms. DAKAR: Well; if you'll yield, I havealready iridibated that I will submit for the record the number ofcomplaints that FDA has gotten: It is a computerized list and 30 perCent of themare over 55. Maybe you dolft consider that older Americans.We Mire had some disability hearings where our witnesseswere 30 years old. But nonetheless, you know, statistically in termsof the complaints and the numbers who have called the_poisoncontrol center, WhiCh is part of FDA, consistently it's a tremendous numberof older Atheri= cans So this is an appropriate committee to conduct it. But even if it weren't; shouldwe not be concerned abbiit tlibse under 55? Mr: BILIRAKIS. Yes. Well, I've made thatcomment. MS. OAKAR. Right - Mr. BILIRAKIS._ And I certainly think thatwe should be concerned: I don't like the age 55 level, quite frankly,beCaiiSe I'm fast approaching it. I'd like to raise that; maybe, bya few_yeara. I understand that PPA has beenon the market for better than 40 years: Is that correct? Dr. SILVERMAN. Approximately_ 50years; Mr. BILIRAKIS. Approximately 50years. Has it been under attack, under the onslaught; going back to Mr. Lantos'word, for that period of time? Dr. SILVERMAN. No, it has not been. Mr. BILIIIAKIS. It's just a recent thing? Dr. SILVERMAN. I think only within therecent past few years that it has received a tremendous_ onslaught ofattack. Up to this time, and now, phenylpropanolamine -has beenfreely available in any pharrnacsr, and as a pharmacist I can go back -to the timeI went to college; It never was a prescription me-di-catkin. Italways WaS an over-the-counter medication: You can purchase itin your pharmacy today under the original brand name, cf?ropadrine; If this drug were used; for example, promiscLotialy,as has been Suggested by some other witnesses; the pharmacistcould never stock the original product on his shelves. For all intentsand pur- 218 214 poses, it is not used promiscuously.Neither IS it abused. And Dr. Winiek testified to that The drug has received critiques, if you will; only within the last, oh, perhaps 4; perhaps 5, years. But the studies that-have been reported are not controlled studies. They are anecdotal; case report type. Invariably the study will turn out to be either adeliberate overdose, where a person ingested a handful of capsules, oringest- ed a deliberate overdose in combination withalcohol, or took, as one of the earlier witnesses testifiedtoday, a polypharmaceutical type of preparaticin where phenylpropanolamine wascombined; for example, with an antihistaminic. Antihistaminics are well known to evidence bizarre reactions in humans when taken in overdose. PPA has been under attack; if you will, only in the laStfeW years: The number of safety studies onPPA go back to the time it was first brought out onto themarket; and that was in the late 1930's. It has been studied in animals since that time and it never would have beeii brought onto the market in the first place; re- leiiSed by _the FDA, if you will, if it were not a safe drug. While the FDA, in 1962, I think, after the Kefauverbill was passed, required new drugs to show both safety andefficacy; up to that time a drug would appear on the market onlyif it were Safe. The fact that phenylpropanolamine was marketed, aswell as many, many other drugs beforethat time; indicated without question that FDA had reviewed it_from the standpointof safety. From the standpoint of efficacy, in the last several yearsand going even beyond that, dozens of studies; wellnigh 50-odd studies, have now been completed, showing phenylpropanolamine as anef- ficacious drug. And I believe that none of the witnesseswho pre- ceded this panel testified or indicated thatphenylpropanolamine was not efficacious. They all said it wasefficacious. It would cause a decrease in appetite. And if the question of safety has arisen, it isonly because of anecdotal studies. And if the question of safety ispointed out in terms of a so:called controlled study; thatstudy, completed in Aus- tralia, was not done in this country and was usedwith a so-called phenylpropanolamine which was never identified asthe same drugand let me use a tongue twisterthe samestereoisomer, the same actual phenylpropanolamine,that is used in this country. You can take this chemical and produce approximatelyeight dill ferent modifications of it Some modificationshave greater effect; some have a lesser effect. The product that was used in Australia, from atleast the package indication; showed it tobe a phenylpropanolamine of a different stereoisometric characteristic. Mr. &MAXIS. But Dr. Silverman, with an answersomewhat briefer than this last one, I wonder, could you tell us veryquickly Why do you think, that PPAand I'll continue to usethe simpler termhas been under attack during these last3 to 4 years? Why is it under attack now? Dr. SILVERMAN. I can offer a speculation.I believe it has been under attack because, for whatever reason,there has been the -pro- miscuous promotion of thisproduct in combination with caffeine and ephedrine as a so-called high drug.Mail order promotion has

219 215 hurt a lot of legitimate drugs. This preparation has -beenunder attack because of the so-called look alike problem which is stillnot yet controlled. I can, and I have done this, purchased through mail order;prep, arations containing phenylpro_panolamine and caffeine, both of which are in overdose. In other words; the- tablets containedmore PPA and more caffeine than are permitted by law. This is where the real problem is and this, I would submitto the committee, with all due respect, is where the attention should be placed. If you can stop the mail order promoters from promoting the illicit, illegal use of the stimulant effect of these look alikes, the problem, as we think we believe it to bea problem; will vanish. Mr. BILIRAKIS; Very good. Dr. Coons, I know you'revery anxious to comment. Dr. COONS. Oh, yes. I just want to comment, again,on the placebo effect. Where you have a look alike,you are going to have an act alike. Just by the powers of suggestion. And this is precisely where animal studies are extremely important. My rats showed that there was absolutely no euphoric or high effect of phenylpropanolamine. PPA is chemically related to dexedrine. But whereas dexedrine, or d-amphetamine, produces a great high in rats; phenylpropanolamine emphatically does not. If anything, it does slightly theopposite, Mr. BILIRAKIS. It sounds like our attention; maybe; should be focused to the look alikes and the transportables. Dr. SILVERMAN. As a scientist who has been an academician for upwards of 30 years and has spent his career teaching pharmacy students_and medical students, there isa real problem with mail orders. There is a real problem with look alikes; and I believeI think it was Dr. Schwartz who said that the smaller companiesare really not paid attention to; The bigger companiesare. By careful regulation of the smaller companies, the problemsas we think we perceive them will vanish. There is no problem in the American marketplace today with the responsible and correctuse of anorectic preparations. Ms. OAKAR: Thank you; Mr. BILIRAKIS. Thank you. Ms. OAKAR. Let me ask a few questions. First of all, PPA did not meet any safety test before 1962 because it was exempted and came on the market before the Food and Drug Act. Dr. SILVERMAN. Ms. Oakar, I'm sorry to interrupt_you but there were several safety tests that were done on PPA before 1962: Ms. OAKAR. It was never approved by FDA in any way, shape,or form. It still isn't. Dr. SILVERMAN. It never would have been released andnever v Quid have been placed onto the market without testing for safety. Ms. OAKAR. That's one of the reasons we wanted FDA- here..-We wanted to ask FDA why it allowed this drug on the market? Why aren't you asking the same questions that victims, like the 61-year- old woman who testified she had a stroke asked? She didn't order that pill through the mail, although we had the Post Office testify. That woman took a very well known product and bought it in a drugstore. 220 I 216 Dr. SILVERMAN: But what we don't know is whether or notthat person was taking any other kindof medication: OAKAR. We asked that and she said She was inperfect health: All of the victims, and We purposely tried toselect people Who had no other medical problems at the time, werehealthy. Let me ask all of you, and I think it's animportant question, have you been, in any way, paid by the industry,Cor your services? Dr. SILVERMAN. I'll start that off. I've done a lotof Studies on phenylpropanolamine. The first study -I_ did oniihenylptopanola- rriine nobody paid me. I was a poor strugglingacademician. I did What I thought was ivory towered research. I still dowhat I believe is ivory towered research. The study I did required me to work considerablyto find volunteers. It took an awful lot of time, an _awfullot of sweat, and -required me to in terms of time, months to do astudy that with a little bit of support I could have completed very, veryquickly. Ms:OAKAR.Are you paid by the induStry? Dr.SILVERMAN.Yes,I am_But only _from the standpoint Of having the study supported. That's all. We're talkingabout expenses. MS._ DAKAR. That's all right: That's fair. Iunder-stand it. I know it's hard: Is there anybody who is not paid by theindustry on this? Dr.CONTE.Madam Chairman, may I say that I have doneother studies for other companies and I don't say I gotpaid: They gave a grant and out of that grant I have to pay thelaboratory, I have to pay the nurses in my officeiI have to pay the rent, and of course for my time Mit, the thing-that is important to me;and I'm a clinician, I am not going to use something thatI don't know anything about: Ms.°AKAR.That's right. Dr.CONTE.And I'm not going to continue to_ use somethingthat is going to hurt my patients. Because it isjust counterproductive. MS. OAKAR._And most patients who buy over-the-counterdrugs don't have access to a doctor. Dr.CONTE. OK. OAKAR. They don't go to a doctor to tellthem Whether or not to_buy :diet drugs. DrCONTE.Right. Ms.OAKAR.They go to you. They're lucky if they have your constant care. Dr. CONTE. Wonderful; but -- Ms:DAKAR:That's very atypical. Dr. Cd&I.E. But why did I do this study? M.OAKAR.That's right: Dr:CONTE.Because as a physiCian I also have theresponsibility to the people that live in my area: Youknow in Ms.OAKAR:My mother is from your hometown.Beaver; Pa: That's a beautiful area. De. CONTE. Do you know where Boardmanis, Boardman, Ohio? Ms:OAKAR Isure do. It's wonderful.It's great: CONTE.I happen to have another place over there.Mit Ms.OAKAR.But let me ask the question again. Isthere anybody who hasn't been paid by the industry?You have not been paid? 217 Dr. BRADLEY. Of coursewe get paid. We have our overhead and all-our expenses.- Ms. OAKAR. Oh, I see. _ Dr. BRADLEY. But one thing Iwant to point out We don't get paid on how the resultscome out. I've done a lot of Clihical studies and I would say 60 percent comeout negative for the drug company They're highly impartial. Ms. OAKAR. And here's the problem;not just with thiS dfug. The drug companies have the opportunityto submit whatever studies they want. They don't have to submitthe StUdida that don't prove; the way they Want them tocome out; Dr. SILVERMAN. Up toa _point. Let the comment on that; please. Up to a point. With the initiation of theinstitutional review boards and the review_by peer review committees-of all studies that are done by internists; by clinicians, wheneverhuman patients are -involved, the FDA is aware of whatstudies are ongoing and what happens with the results. It's an open book. book. It's an actual open Ms. OAKAR. That's whywe wanted them to be here todas, be cause we wanted to ask the FDA how they could possibly kind of thing. allow this _ Dr. COONS. I would like to make a comment too: I was asked by Thompson to run this study on rats,to doubleoheOk on Ms. DAKAR. Did you get paid? -- Dr; COONS. I got the expenses for doihgthe study; that is; buying the rats and, you know; research isexpensive. I had that But Iwas asked to do this to check onsome other_ studies that have been done by Professor Hoebel at Princeton.He has done studies on PPA in rats and in humans. MS. OAKAR. Right. Dr. COONS. And it wasa doublecheck. And -I must say that I would be very foolish professionally_to do anything that was not going to be correct, andas a scientist I certainly mouldn't. Mr. BILIRAKIS. Would the gentlelady yielda moment? Ms. OAKAR. I'll be happy to yield, briefly. BILIRAKIS. Briefly, yes. I accept what these gentlemensay in the same spirit, in the same sense of credibility, as I accepted what the previouswitnesses Said. Ms. OAKAR. But there'sa major difference; though. The previous witnesses are not paid by the drugcompany. Mr. BILIRAKIS. Well, they weren't paid by thedrug companies. MS. OAKAR. Yes. Mr. BILIRAKIS: _I have attended hearingafter hearing after hearing with this Aging Committee and other committees,and I assure you that someone selects these _particular witnesses forwhat they are going to testify to. It isn't a matter of reachingout and grabbing somebody off the street, not knowingwhat they are going to testify to: _ Ms. DAKAR. That's correct. Mr. BILIRAKIS. So, there isn't complete objectivityin any particular area. I doubt very much thateiccuseme; ma'am I doubt very much if the gentleman testifying from theJohnS HOPkihs SChool of Medi-

c, (.4 A 222 218 cine, for inStance, or some of these other universities, aregoing to testify falsely or in some, unilateral way. I thinkthat their reputation is certainly goodI don't think they need anydefense on my part. But I think I had to say that. I've had the same feeling, sometimes, regarding .3omeof the witnesses that we have had up here whohave been hand picked by whomever, certainly not by this side of the aisle,and this should not be a partisan type of a thing. MS. OAKAR. It sure isn't. Not when people arereally in terrible shape. Mr. BimitAki§. YeS, but there have been handpicked witnesses. Ma. DAKAR. Let me- read from the FederalRegister. They still haven't made any definitive regulations or come outwith a final draft or monograph. But this is fromFebruary 26, 1982, which you refer to Dr. Silverman. Some of you indicatedthat you_even_give PPA to heart patients who have high blood pressure.Am I correct about that? Well; let me refer to the Register, which severalof you have mentioned kind of proves that they concluded thatit was safe and effective: PPA by obese perSonS with hypertension may significantlyincrease their risk of heart attacks, stroke, and kidney failure, andconsidering the positive aasociation between hypertensive and obeSity, the increase in riskbecomes very evident because obese people are most likely to use weight control products. They further conclude that in the studies that werereported to them, with only using 50 Milligrams of PPA,and most often it's 75, 11 percent of the subjects given one singledose- of 50 milligrams developed hypertension and a single dose of 85milligrams in a time-released product caused hypertensionsometimesseverein 32 to 33 percent. And what is fascinating to meis when you read the body of the Register you really get alarmed.And then you read the conclusion. I *anted to ask FDA, didsomebody else write the concluSion? Because surely what is in the body ofthis Register does not match the conclusion. Now, a conclusion, from my old English_teacherdays, is supposed to either summarize what's in the bodyof this prepared p: elude to a monograph or it'sSupposed to form some conclusion based on what's in the body of the material. I can't,for the life of me, figure out who wrote the conclusion becausethe body of it is a lot different. Furthermore, you stated-- Dr. SILVERMAN. May I comment on that,Ms. Oakar? Ms. OAKAR. Surely. Dr. SILVERMAN; May I very shortly, verybriefly? Ms. DAKAR. Sure. Dr. SILVERMAN. Because rm pleased toindicate to the panel that at least one of my studies hasbeen written up in that preamble that you just described. What that preambleindicates is that it al= ludes or describes anecdotal studies,the studies that we have discussed over and over again today, a fewpatients; one patient, and So forth. And what the FDA did, andI consult for the FDA also, what the FDA did was ask the drug industry,if you will; as well as investigators,_whomever they might _be, to carry out safetystudies, do more studies; and this is one Of the reasonswhy we're here.

- ._h 223 219 Areas discussed today represent newer studies that have been submitted and these investigators with whom I have come today have carried out some of these studies. Indeed; Dr; Bradley's studies done on hypertensiveswere dOne in response, in partial response, to this request; Ms. OAKAR. To this study? Dr. SILVERMAN. Yes; Mg. DAKAR. Let me comment on the fact that we talked about what you call this new onslaught of PPA. It's really not newthe numbers of cases are reported year by year We've changedour attitude toward alcohol. We've changed, our attitude toward the manner in which cigarettes are promoted in this country. We've forced labels to be readable. That's only happened in the last few years. And we certainly have changed our attitude toward other drugs. My own feeling, obviously, is that these over-the-counter drugs leave a lot to be desired, that the advertising is hyperbolized. For example, in California there is a -case that the attorneygeneral won, that was settled out of court. You mentioned that it's not a stimulant; Our books from the Library of Congress -call it a atim= ulant. In California it's mandated; am I correct; that you call ita stimulant, because California won that case and settled out of court? But in Washington; D.C., you don't have to do that. Why did they settle out of court if it's not a stimulant? Why did they settle out of court with the individual who was a victim of the stroke today? Dr. SILVERMAN._ I don't know why the company settled out of court; because I, am not a lawyer and neither am I competent enough to be able to provide you any type ofan intelligent statement in reply toyour question. But as far as -its being a stimulant, Dr. Schwartz, who was not part of this panel, I think, provided us with the answer. He said that many chemicals have similar struc tural resemblances, but they have different pharmacological ef= fectS. The reason why PPA is classified; as a so-called stimulant is because it is structurally related to the amphetamines. But it is not an amphetamine inducer in terms of its pharmacological effect: Now, Dr. Schwartz, who I believe appeared at the invitation of this committee, indicated that to you earlier. And I would respectfully say that the studies that have been sponsored by industry validate- that statement that it is not a stimulant. The studies at Johns Hopkins have indicated that it is not a stimulant; and these studies were done in the lower animal, the primate, as well as in the human. Mg. OAKAR, Let me thank the panel. I think what we're trying to do is arrive atwhat I'm trying to do, is_protect the consumer. I'M here to protect the consumer: And if that means thatwe -keep safe and decent drugs on the market, that's what we need. We realize the contributions of certain drugs. We also know that 66 percent of all over-the-counter drugs are not safe or effective. I would like to briefly ask your people here, who all look fairlY trim, to come up, if they'd like; and say just a few words. The other committee wanted to be in here an hour ago, so the chairman is going to really be disturbed. 220 Dr. Bradley, I meant to ask youand I forgot to, for therecord; how many people you usedin your hypertensivestudy? Dr. BRADLEY. We 11; because wewere concernedabout all of this information on hypertension, wedid a pilot study of 10patients. MS. DAKAR. Ten People? study of 60, Dr. BRADLEY. Correct.Now We've started on another of which I have completed28. don't have low blood pressure,_dothey? MS. DAKAR. I see. They It's Dr. BRADLEY. No, no; theyhave to have high blood pressure. part of the protocol. MS. DAKAR. I see.Would you like to brieflYintroduce your people? Ms. Bar- Dr. SILVERMAN. Let mebriefly introduce the consumers, Schreiber, Sr., and Mr. JamesSchreiber, Jr. bara Ritz; Mr_James statement; MS. DAKAR. Right. We'llhave time for you to make a OK? STATEMENT OF JAMES SCHREIBER;JR. Mr. SCHREIBER, JR. My nameis James Schreiber andI was 19 years old whenI tried the productDexatrim. I weighed about 235 230, And I had a. 38- to40-inch_waist. I poundsno, 230 pounds, 225; appetite. The rest took the product and itWorked. It suppressed my keep a good diet and tomaintain it And in 3 was up to me, to In the next couple ofmonths I lost months I loSt about 60 pounds.- And I cut my 25 more pounds anddropped 85 pounds altogether: waist size down_to 32 and I nowweigh 155; approximately. MS. DAKAR. You look good. Mr. SCHREIBER; JR. Thank you. off, going on 2'/2 years;I never felt high And I've kept the weight high from that from the product. I reallydon't believe you can feel Ms. DAKAR.. Did you feelnervous? Never. Now, but I'm not onthe product. Mr. SCHREIBER, JR: the drug industry? MS. DAKAR. Right nowAre you being paid by Mr. SCHREIBER, JR. I've neverbeen paid. M. DAKAR. Neverbeen paid? Mr. SCHREIBER; JR. No. voluntary. Well; that'sgoOd. Ms. DAKAR. Totally few words for thecommittee? Be- Would your father like to say a and I apologize cause we really areforced to get out of the room about that; Mr. SCHREIBER, SR. Yes,I know. STATEMENT OF JAMESSCHREIBER; SR at Trenton State .1'...Mtg SCHREIBER, SR.I am assistant professor College in Trenton. What my sonsays is Correct.It's hard to be- 230 pounds. I weighedabout 185 *Inds lieve that he did weigh decided. to try it I loSt about and after seeing himlose the weight I 165, and as a 45-year-oldman I Wasparticu- 20 pounds; from 185 to effects; and I can larly worried abOut highblood pressure and side honestly testify I had_none, nonewhatsoever. Ms. DAKAR. Great. HOWabout you?

425 221 STATEMENT OF BARBARA RITZ MS-RITZ. Hi; I'm Barbara Ritz; At age 40 I weighed approximately 160 pounds and I was in great danger of high blood pressure and, I was told, a candidate for a stroke. A member of the family is a physician. He told me to take the Dexatrim. He said, "Barbara, its easier to get that weight down and get yourself under control by taking the Dexatrim rather than being that much overweight and having to worry about a stroke." I took the Dexatrim. I did not have any adverse reactions. I feel better. I'm like a new person. And I have no blood pressure problems at all right now MS. OAKAR. None of you have ever been paid in any way? MS. RITZ. No No: Not at all; Do you have any questions for us? Ms. OAKAR. Good. Great. Mr. LANTOS. How much do you weigh now? Ms. RITZ. 110 pounds. Mr. LANTOS. So you dropped 50? Ms. RITZ. Yes. Mr. LANTOS. Fifty-some pounds. Ms. RITZ. Yes; in 20 weeks. Ms. OAKAR. You are a lot luckier than the _other witnesses who took pillsthey had hypertension, cerebral hemorrhages and strokes, and permanent damage from ingesting the pills in prescribed dosages, Thank you all for being here today. I sincerely hope that Con- gress takes action and sees that over-the-counter diet pills containing PPA, which is neither effective nor safe, are taken off the marketor at the very leastthat they are made prescription drugs. And especially, I call on my colleagues to think about consumers and their need and rights to be protected. I would like to thank staff members of the subcommittee and my office_ for their dedicated and hard work in preparing for this hearing.I especially appreciate Millie Vinicour, who identified this issue and oversaw all of the groundwork, Daniel Rosenblum an ex- traordinary intern; who assisted in the extensive analytical efforts; and Nancy LeaMond, who drafted proposed legislation to improve the performance of the Food and Drug Administration. [Whereupon; a 2 p.m., the hearing was adjourned.]

226 27-436 0 - 84 - 15 APPENDIX 1

5B Survey finds more thana It of Pinellas elderly misusing medicine ay PAT POSTER basted) because bet medicine is the patient is taking. The doctor might w. Patanaosig Times luffiVrtne mesithuhariap." aiiii_unkiinwiiiglY_preaciribe_i According to the report on the rine that will interact with the other Mon than helf the people age 60 survey, "Medication UtilAbuse drugs to cause iide effects. and older surveyed by Pinellas Antonithe Pinelbascounty Elderly," Ma. Morck emphasized the need Cithitg _thult_prograns__wers Uking people 60 and older makeup 9 percent for communication between elderly their medicine in a potentially dan- hf thenittionTel papultitins_htit_pur, pessons_a_tbeir _doctors. She_ said gerous manner. chase 25 percent of all prescription when doctor prescribes medicine, an The !Survey byOperation_PAR drugs. The report said -the elderly are elderly personshould fully inform the (Parental Awareness and Responsi- 35 percentof the population in Ping- doctor of alitho_drugs the patient is bility) indicaW teat elderly persona les County. taking, including "that little shot of engage in a variety donuts medica- Of the respouVista to_isurvey, whiskey or these two glasses of seine tion practices. They include using old 68A% were commend' prescription Wren at night as a home remedy." prescriptions, gUrW,_ preacn:Ptione medicine. Ms. Morck said any elderly Ma.- Merck said meet of there with friends and taking over-the- person who _taW-more _thast_two lear-th by_dhg_tsXrTiptinies aboutdrug counter drugs at the nametune tusy medications more than onceday is effects has concerned younger people, take prescriptions without consulting especially at risk. The numbier of dif- but the effects of drugs in the elderly doctor. ferentlustaiptionsstad the number of can be quite different from those in Although PAR cim-foiie times they are taken contribute to the younger patients. work concerning drug _problems potential for mune. among young pupils PAR has oper- AGE AFFECTS_ the_ rate at atTd a program I _the_elderlY IWO ELDERLY PERSONSpneral. which drugs are metabolized in the 1979 because of concern about drug ly do not like to take chugs unless they body and how quickly they are elm,. misuse by the Warty- Mvato.Whentheyareilltheyieulto jilted. AGO, she laid, older_ people _P_AR conducted the survey in search for over.ths-counter drugs in- generally eat less than younger people March and April. A questionnaire was stead of going to &ear, aid Dr. do. given to 270teefrinditits atrobiregati Lou_Salerno._ PAR Community Theestinthabits of older persons d i n centers and at county daycare Education Director. can cause complications. "Suppose," centers. A ahorter questionnaire was The misuse of over-the-counter MI.Morek SitA,"thidisttrittellithe atniatisined tO a5 pawns at _the drug. is one of ths biggest prellems. patient to take two pilla after meals. Senior Citizen Shawnee* of Services. Some elderly pa Gentatake too men thinking the patient eats three regular TELE LARGE amount of medi- or -take the wrong kind or, most fuels &day. This cars be a verydiffi- cult or confusing schedule fora patient cine the elderly take isbasic our ei saisously,eoverlUounterdrup along_ with presaiptioo medicines who does not eat threerimes a du (or) the problem. eats yen, little when he does eat." The survey showed that the elderly without consultinaga doctor about this PAR's educational presentations use a disproportionate ansountolbOth multitudeo[ms see Morethan40 percent of the respondents said they made_ by_Sgemo. encourage good prescription and over.the-cowster record-keeping by the elderly and drugs. Thu increases the risks that never conadlthd docttrisUitus. int overthe.courster drugs with pre- communication with hegth care pro- arise_from_the COMbinistion_ofrinsgs fessionalssnd with family members which MO result in effects that neither scriptions; 30 pe use said they some- who are caring for them. drug alone would cause. twozwrdutagost *joint meet- 'The report listed frequeotkused Salerno said he will address "any ing of the U.S. Senate and House aging overthe-counter &kis that can be group of peopk, any day of the Wink. committees. witnesses told_about hexertkers to the elderly: day or night for 15 minutes or three physical Jul mental side affects that laxauves, diuretisitamios,mtadds hours, whether there will be 10 people elderly persons have experienced from eraugh there or_10,000." mause_d_chkgs. utcluding Mee Doctor-shoppiek caateauum In addition to lectures. PAR will alcm of in...enable senility. Actually, Isificantly to the rith of misuse. Provide any elderly person a free the Problem was exc:seavely fiigb The elderly: - Ms.Aforek_said. often booklet ailed "Passport to Good doseacgmedications. have more than ose glossa and will Health Care" in which a person can Mary Ann Morth, PAR- prop-am go Grim_ doctor _ torrostW_getting a record the medicine he in tazog;_the eval**_thd_ atitCuir_ Of_the_ Iota different prescripUoo from each. A schedule for use; the color. shape and grogferePort, said young people need patient often (that° tell each doctor strength of each drug, and the direr to be ',minded that "Grandma i-ould Shot other cloture/ hatte_preithlad tions and warnings foresch one be a little slow (or unusually an- and what overthe-o' mutat medicines PAR can be reached at 527.5866.

( 223) 224

MEDICATION USE /ABUSE AMONG THE PINELLAS COUNTY ELDERLY

June 1983

Operation PAR, Inc. Elder/Ed Program 6613 49th Street North Pinellas Parks Florida 33565 (813)527-5866 225

Operation PAR is a comprehensive drug abuse education,_ prevention and treatment program. Drug misuse and abuse affects all_age_groups.Most drug abuse education, prevention and treat- ment_programs traditionally have focused on adolescents and-young adults; Howev_ri_the problems of medication misuse among older Americans are serious and complex.

Medication is a valuable_therapeutic_tool_for the_care_of the elderly: Research_ ndicates that as a_groupi_the_elderlY_ tompose aopteXiMately 9% of the national populationi_yet_consume approximately 25% -of- all _prescribed drugs; In- Pinellas- County; the elderly constitute -34.9% of the_total_population;_ The'relatively high rate-of medication-use in conjunction with the_per cent of the total population along with_the dysfunctional aspects of the aging process place the elderly "at-risk" With respect to the potential misuse of prescription and over-the-counter medication: In_1979i as a result of interest in drug mismanagement behaviors of_the_elderly, Operation PAR began the Elder/Ed Pro- gram; As the program_developed, it became evident that_no systematic attempt_had been_made_to identify the medication /drug use needs of Pinellas County_elderly. _An_initial survey_was con - ducted -to- attempt -to gain insight_into_the_medication concerns And behaViors of the _elderly; _The_survey_was crudei_but provided a !JAMS for program development._ In_order_to_enhance_Elder/Ed services and more accurately_define_the medication_misuse_needs of the elderly, Operation PAR redesigned the initial instrument to provide more comprehensive information into the medication practices of Pinellas County elderly.

Methodology Measuring the_severity of the medication misuse problem among the elderly is a complex task. The survey was designed to secure information regarding_the_demographic_characteristics Of the respondent, his/her general_health,_prescription drag Use, as well as the use of over-the ,counter_medication.__Two instruments we developed; Theionger_questionnaire included 35 questions and was administered to Neighborly_Senior_Service recipients.- The-total number of respondents (N)_in group was 270. A shorter version was_developed_for_use_at_the °Senior Citizen Showcase of Services." The total number of respondents (N) in this group was 85. In order to make the survey as easy to complete as possible, all questions required a forced choice response. The forced choice format enabled participants to check the-appropriate re- sponse_with an option to explain a notation of "other'. -Both instruments_were presented in large bold face type on brightly colored paper to ease any reading problems.

229 226

The target pop:Ai:don was-Identified asPinellas_County residents 60 years of age or older. In Order to_develop_a_sample group_representative of the_population, threemajor_subgroups___ 1)congregate dining recipients; 2) county_day were identified: "Senior_Citi care clients; andSlat-large respondents from the tens Showcase of Services,! The congregate and day care_respon- dents provided PAR_with_the opportunityto make brief introduc- toil statements regarding_the surveyi_thenread through the in sttUMent question -by question.___AVeragecompletion time -was 15 Citizen minutes. The at -large group_surveyed_at_the Senior administration- Showcate Of- Services presented_a_different forum concern. The-Showcase is an annual day long informational showcasing elderly services available_in PinellasCounty. Gene-- rally, the ShOWdate provides information_outreachto approximately 3;500 elderly tititent: Thd_instrument_for_administration at of be- the Showcase had to be concise with a completion time tween 1-3 minutes. The abbreviated-version of_the_questionnaire included questions in all areas of interestthat can be compared to the other subgroups. There_was_a_total_of_356 survey participants; _57.9%(206) of the_respondents_were_from the NeighborlyDining Program; 18.2%_(65) of the participants were_enrolled in theAdult Day Cate Ptegtam;_and 23.84(85)_completedsurveys at-the-Showcase; According te information _secured_from_the_TampaBay Regional- Planning COUnCil, there were7,317_recipients_of dining services and 591 achilti in day CareAuring_1982.__In_lightof these figuresA_PAR survey sampled approximately3% of the congregate participants and 11.2% Of the daycare_participants, Surveys were distributed at the NeighborlySenior Service tenters in conjunction with_an Elder/Ed presentation._Staff_was available to assist participants whoseeyesight was insufficient_to complete the_survey. It is of note that severalparticipants indicated an_inability to read the survey,but were in total control of their medication. -Congregate and_Day Care_sites_werechosen -in- order -to Attain a representative_countyr_wide_sample. The following sites were utilized in the survey sample:

Di-n4-noProgram St. Pitettbiitg-Beach Civic Hall 1500 Pass-A;;Grille Way St. Petersburg Beath Mirror Lake Christian ChUtth 737 3rd Avenue North St; Petersburg Rogate Lutheran Church 2447 East Bay Drive Largo

n 227

Gulfport Presbyterian Church 4201_6th Street South St; Petersburg

Mount_Carmel Baptist ChUrch 1014 Pennsylvania Clearwater

Day Care-

Lealman United Methodist Church 4090 58thjivenue North St. Petersburg

Palm Harbor_Day_Care 1550 16th Street Palm Harbor

Woodlawn_Presbyterian-Church 1235 -26th Avenue North St. Petersburg

Survey results will be reviewed by participant category and overall. Base data charts which include_individual question tabulations can be found in the appendix._ Results_will_be grouped according to the type_of_question;_deniographics; prescription drugs; oveNthe7counter medication; unsafe medication practices an at risk" factors;

As a group, studies_have shown -that elderly consumption of medication is_disproportionate_to_their_percentage of the total population; Despite the relatively high rate of consumption, the elderly -arehesitant-to discuss drug-use or misuse. There appears to be an inherent reluctance to identify medication as drugs. In the development-of the survey, care was taken to use the term "medication" instead of "drug(s)" whenever possible to reduce the anxiety of the elderly respondent.

Additionally, it should be noted that as survey results are reported the total number of responses will vary. This variance is attributed to two major_factors.__Several_questions are selective. An example- is -an- inquiry as to- whether the respondent_uses_prescription_medication. A negative- response would_not require the respondent to answer additional questions regarding prescription medications._ The second_factor_contri- bating to_incomplete responses is the-misconceptions that surround the_eiderly_perception_of-drug use and- the- interest of others in their medicating-behaviors. Overall, the response percentage was approximately 84.3%. This means that on an average, participants responded to 30 out of the 35 questions. Information regarding completion percentage per question is provided in Appendix 8.

1/4 c*231 228

III. Profile of Survey'Participants- The majority of individuals surveyed were women (60.10. Approximately 7.6% of the respondents were non-white. The ages of respondents were fairly well distributed: 34.4% averaged 60-69; 39.3% averaged 70-79; and 26.3% averaged 80 and older. Most of the elderly surveyed lived alone t48.1%), oelY 2% re- sided in some form of group care. The variable of_living alone can be considered a "risk" factor with regards to medication mismanagement. 76.1% of the individuals surveyed were participants in a county social service assistance program sponsored by Neighborly Senior Services. The remaining 23.9% were elderly who completed surveys at the Senior Citizens Showcase of Services. Additional information was secured regarding the respondents financial situatien. Of the 356 respondents, 315 or 88.5% indicated receipt of Social Security benefits. 92 or 25.5% of the respondents cited receipt of multiple financial resources. Respondents were asked -if they considered_themselves to be under regular care of a doctor. 76.2% of the_Day_Care_respon- dents were under a doctor's care -as compared to_63.8% of_the_ _ congregate respondents: -Comparatige figures were_not available from the "at-large" population. Overall,_66.8%_of the elderly surveyed were under regular care by a doctor; -The remaining_ 33.2% of the respondents not under regular-doctor'' _s care could respond to discomfort or minor illness with-a self-medicating practiceThis situation could place them "at risk" of medication misuse. As stated- previously, the elderly consume adisproportionate share of over- the - counter medication. Respondents were asked to indicate how many_of_a listing of r)mmon ailments they_tend to suffer from_regularly.__Of the_ten_conditionS presented for eevieW; -.only-three (arthritis; high blood_pressurei_and chest pain) were Of the variety generally_considered_to_requice_im- mediate or prolonged medical Attention;_ The_remaining_seven_ were common somatic complaints ranging from headachesto_gasi_ _ indigestion. Information was available from only the congregate and day care groups.

Frequencies can be viewed by percentage of- the -total com-_ plaints_cited_or_by_the frequency of the condition by the total number_of resondents Information was also available on-multiple complaints.__200 or 73.8% of the respondents identified at least one complaint; _58;5% of_those_who_cited complaints identified- arthritis; The conditions in rank order by frequency Of identification are as follows: 229

Rank *% of Those Responding Who Cited Condition 1 Arthritis 58.5% 2 Colds 49;5% 3 Leg_Cramps 48;5% 4 High_Blood_Pressure 45;5% 5 Gas/Indigestion 30;5% 6 Coughs_ 25.5% 7 Headaches 24.0% 8 Stomach Problems 19.5% _9 Flu 19.0% 10 Chest Pain 15.5%

*Percentages were figured by_taking__the_percentage frequency of the condition of the total who responded. The average respondent cited 3.4 different complaints.

Respondents were then asked -to categorize their general health as_either poor; _fair, good or excellent. The Day Care respondents tended to depict their health in more negative terms than_those -at the congregate sites. In general, approximately 85;5% of -the respondents cited their health as either fair or goo-: -The extreme categories of poor and excellent accounted for only 5.2% and -9,31 respectively.

Frequency of doctor visits was fairly evenly _distributed. The most frequently cited response was "twice a_year' (33.0%). The second most frequent response was "other"_(25.4%).__Upon_re- view of the "other" categoryi_the_responses were either as needed", "when sick" or "quarterly."

Another- gauge of the general health of the survey group was derived from self reported sick days in the past two months. The average number of sick days per respondent was 3.4 over the two month period.

The final demographic or descriptive information on respondents dealt with the use of prescription medicine. 68.4% of the respondents indicated current use of prescriber medicine. The typical survey respondent was:

Female Aged_7049__

Living_alone__ _ Receiving social security Under regular- doctor=s care Suffers -from 3 somatic complaints (probably arthritis) Considered their health "good" Sees their doctor twice a year Taking prescribed medicine.

233

1 4 4 L 230

IV. Prescription Drug Use Nine survey questions dealt directly with_prescription drug use. These questions begin to -deal -with the "at risk" dimension along with reviewing unsafe medicating practices. Additionally, most of the prescription drug questions were asked of all three subgroups.

_As_ stated previously 68,4% of all respondentstakepre - scription Day -care participants cited a --higher percentage involvement_with prescription medicine (78%) than congregate dining recipients (65.5%) Prescription-drug use for the elderly patient often involves multiple prescriptions -and ccmplicated_medication schedules. Both the number Of-different_medications_used_and the number of times medicated dailic can heighten the risk_potentialfor misuse. Survey participants were asked to- cite -the total_number_of_dif- ferent prescribed medications-being utilized; The_thred_sub7 groups reported significantly different results; 69;3% of the congregate dining participants citing-prescrtption_drug_use, utilized from 1- 2 different medicationsand-35.1% used 3_-_4_different medications. The day care clients cited 46;8% in the 1- 2 category and 44,71, inthe 3 - 4 medication category; Overall; 62% of those surveyed were taking 1 --2-different prescrtption_medreitions. With respect to risk, participants who indicated prescription drug use of three or moremedications concurrently -were considered "at risk". For the populations surveyed, 38% were considered_"at_risk" based uponthe use of three of more different prescriptions; A common condition associated with_the aging_processis forgetfullness and confusion.- Complicated medication_schedules create an additional "at risk" condition forthe elderly patient. The more frequently a patient has to medicatei_the_higher the_risk or error. In all of the subgroups-, the majority of participants medicate two or more times daily._ Overall;only 37;7% indicated a once a day medication schedule.

FIGURE 1 NUMBER OF TIMES MEDICATED DAILY

2;3%

37.7% 62.3% 37.7% low risk of risk of daya mismedication mismedication

Cl 234 231

Combination of-the number of-prescribed medications -taken and the frequency of medication yields a more in depth view of the medication practices of the elderly.

Risk with regards to the number of prescribed medications taken and medication schedules is defined as follows:

No/Low Risk

1 - 2 medications/once a day Moderate Risk

1 - 2 medications/2 or more times daily or 3 or more medications/once a day High Risk 3 or more medications/2 or more times daily

Figure 2 displays the volume and percentage of caseS by category. The figures indicate that approximately 672-1 of all respondents were_at_some_level of risk with regards 15The quantity of medication_combined_with_a_oomPlicated medication schedule. The information is_also_beneficial_with_regards to program development; Over 89% of -the respondents take between one and four medications between one and fourtimes._daily; _De7 velopment of a dispensing -aide woulde_most_heneficial to this group. Extreme cases could be handl4d individually; FIGURE 2 Cross-Classification Number of Different # OF TIMES MEDICATEDDAILY Medications Taken By ' The Times Medicated Daily t_of 5 OR O M. IOTA' 1 2 ORE

1- 2 A2A5;-lfr./k--MEI NO /LO" RISK: 32.7% a 4 62 MODERATE RISK: 36;2% HIGH RISK: 31;0% 17 *MISSING OBSERVATIONS.= 12

Nom. . 10_0 MORE 3

TOTA 93 64 54 3211111121

*Percentages vary slightly -from- the tables in the appendix; The variance is due to the number of missing observations due to cross-classification.

235 232

Another factor that can increase the risk of medication misuse is the amount of different prescriptions on hand at home. Some prescriptions may no longer be used daily, but could be left over from acute illnesses. 69 -.-4 -% of the participants indicated a supply of 1to 3 different prescriptions at home. 11,2% indicated a total lack of prescriptions at home. The at risk" group. 4 or more prescriptions on hand was 19.4% of those who responded.

An unsafe medication practice common to most people is discontinuance of medication if relief is perceived. This practice that appears on the surface to be innocuous to the general public can have serious effects upon the elderly. 21,3% of all survey participants admitted to discontinuing medication if (in their opinion) their health improved.

If a patient discontinues medication, the question then becomes what is done with any leftover medicine. 63.7% of the' respondents indicated that leftover medicine was draiTded. However. 34% admitted to_saving leftover medicine for later use. and 2.3% indicated that_they would_share leftover medicines with others. Compiling a personal pharmacy and becoming a pharmacist to friends are unsafe behaviors, practiced by 36.3% of all survey participants. Another common medication practice is self-diagnosis. Very often patients phone the doctor's office for -a prescription rather than_make an office visit. However, for the elderly patient thiS could be dangerous. Symptoms the elderly may recognize from the past might be new conditions brought about through the aging process. 42.9% of the respondents admitted phoning the doctor for a prescription.

It has been frequently cited that the elderly consume a disproportionate amount of medication,Additionally. as a group they have been acultured to rely on the judgement of doctors, However, most pharmacological research on drugs prescribed to the elderly is completed on much younger populations. A major concern of elderly serving professionals is whether or not the elderly client is aware of all the possible side effects of their medications. 34,1% of the respondents indicated no knowledge or understand-517f the potential side effects of their daily medication. This lack of knowledge could lead to self-medication of a misdiagnosed side effect as a common non- serious ailment. Lack of knowledge of the potential side effects of medication is another "at risk" factor for the elderly. The average American receives medical/pharmacology "training" daily through advertisements;__The public_is_encouraged_to review their symptomology; assuming the condition_doestOt warrant a doctor's- visit.-and become -their own diagnostician_and_pharmacist: Survey participants_ were asked to identify what they would do if they felt "sick" and didn't go to the doctor; The results of

236 233

the forced choice responses are as follows:

FIGURE 3

RESPONSE -TO ILLNESS WITHOUT percent SEEING A PHYSICIAN 100 90 79.9% 80 5% BORROWED_MEDICINE_FROM FIENDS 70 USED A HOME REMEDY

60 USED OLD PRESCRIPTIONS 50 OUGHT SOMETHING FROM STORE 40 30 203% 20 PHONED: DOCTOR 10 0

'SAFE'BEHAVIORS UNSAFE BEHAVIORS

Only 9.3% of those surveyed indicated they might secure advice from a pharmacist. 10.8% indicated they would phone the doctor for a prescription. These two responses are the only responses that even attempted to involve a recognized medical practitioner. 79-91 of the survey participants involved themselves in some sort of self-dlagnosfic and prescribing behavior.

19.1% of those surveyed indicated that_they would become_ involMith over-the-counter medication_if Use of_over- the-counter medication_is_a_common_phenomena among the elderly; The following_section_will deal specifically with over-the- counter drug use among the elderly;

Probably the most common_unsafe medicationbehavior ascribed to the_elderly is failure to adhere_to_their_medicatiOnSthedule. Participants were asked_if_they_ever missedtaking their pre- scriptidns. 41-6-% indicated that they_had missedself=medicating on at least one occasion._The_reasonbehind_missed medfcation WAS then explored. Participants were given five forced choice 234

they responset. Over__67;1% of_all_respondents indicated-that merely forgOt. Three of the responses_involvedself-dianOtit__ 26-71 of the respondents identifiedinvolvement in self-diahottit 6-21 of the_participants_cited_"other" reasonsfor behavior. "other" missing medIaTion. The predominant reason cited as was that the prescription ran out.

FIGURE _4_ REASONS CITE() FOR MISSING MEDICATION

32.9%

SELF-_ 15.3% DIAGNOSIS FELT BETTER

Respondents were_surveyed as to theirresponse -to an_in, indicated that they would cident of- missed medication 74.81 However; wait until the- next appropriatesfie to remedicatt. 13.2% indicated .:that they would takeanother dose-at Soon as they realized the-previous dose wasmissed. Immediate remedi- frequently occurs among the cation is an unsafe behavior that elderly.

V. Over-The-Counter-Me44-c-ation5 misuSe_among_the elderlyis in- Another area of_medication 44-01% of appropriate use -of over-the - counter medications. participants_indicated use -of -over-the - counter the survey asked if they_usedover-thedrugs. Partitipants were_also 44.5% counter drug§ along withprescription medications.

238 i4A 235

of the respondents indicated concurrent use of over-the-counter drugs and prescribed medications.

Many "over-the-counter" medications can have serious t.:f- fects when used inappropriately for prolonged periods or in conjunction with certain prescriptions. Participants were asked if they tended to consult their physician when using over-the- counter drugs with prescription medicines. The forced choice response options were: never; sometimes; or always. -71-1 of the participants indicated that they either never (41.38 1- or sometimes (29.7 %) consulted their doctor when using over-the- counter drugs with prescriptions.

Knowledge of prescription drugs is initially transmitted by a physician or_other competent_medical_authority.Information sources for over-the-counter medications is varied._ Efforts_ were:made to identify the sources most commonly used by_parti- cipants in relation to over-the-counter drugs._ Across the_ three subgroups, physicians were the-most popular information source for over-the-counter drugs.- Similarly, most relied heavily on advice from the pharmacist as-well as mass media advertising. It is curious that among all subgroups, the information on the labels of the medication consistently ranked very low as an information source.

Figure 5 OVER-i.THE-COUNTER MEDICATION INFORMATION SOURCES RANKED BY PREFERENCE OF USE

. _ 1 CONGREGATE DAY CARE -!-AT'LARGE! -0VRALL--

.... . Source % Source Source % Source: %

Uoctors 34 Doctors 45.2 Lioctors 32.9 DOctors 35,4 . _...... _ _ . Advertising 22.9 Pharmacists 19.1 PWanitaciSts 26.8 Pharmacists 20.5 Pharmacist 17.4 Advertising 11.9 Advertising 13.4 Advertising 18.3 Friends 13.2 Friends 9.5 Friends 9.8 Friends 11.6 Labels 10.4 Relatives 9.5 Relatives 8.6 Labels 9 Relatives 2:1 Labels 4.8_Labels 8.5 Relatives 5.2

239 236

In relation to over-the-_counter_medication_labelingi participants were asked_if_they_were_able_to_read_the_labels_or instructions_._ The_forced choice_responses_were:_ never (able to read);_sometimes_(able_to_read); or always_(able to read). 26;2% of_all respondents_ cited difficulty in_reading labels; This could account for the low ranking of labels as an information source for medication;

Figure 6 ABILITY TO READ MEDICINE LABELS

a ALWAYS 223 73.8%

SOMETIMES 56 18.1% a Experience some difficulty with product labels. _NEVER 25 8.1%

Participants were surveyed regarding their personal use of over-the-counter medications. Eleven common over-the-counter drug types were listed along with the possibility of citing "others". Partic 3ants were asked to think of their medicine cabinet and indi..te how many of these medications they have at their disposa .

Information regarding the most frequently used over,the counter_drugs_was_provided by respondents.__The_most_popular non - prescription drug used by the_elderly is aspirin/pain re- liever: The second_most_frequently used medications_over all subgroups were laxatives/diuretics; _Overall; the five over -_ the - counter drug types listed account for approximately 76;1% Of the entire over-the-counter drug use of local elderly. 28?

Figure 7 OVER- THE - COUNTER MEDICATIONS MOST FREQUENTLY UTILIZEDMEDICATIONS

CONGREGATE DAY CARE AT LARGE TOTAL

Medications Medications Medications. % Medications

As Orin/ . . 243. Aspirin/ ; Aspirin /: . Bufferin ?9;4 2579 Bufferin . _flufferin 27'2 Bufferin Laxativest_ Laxatives)' a?ctiy,.5/__ 17.D 18;5Vitamins 16. Diuretics r.11:retits urai es'.16.3.

.1 Vitamins 15.2 Vitamint 14.4Laicati yes/ Diuretics 154

AntatidS' Cough Med; 11.6Antacids Cough Med. 8.4 Antacids Cdugti Med. 8;4Cough Med:7--13.13

These over-the-counter drugsOrdinarily harmless to the general population can be apotentialdanger to_the elderly; The_drugs_listed ab eve -are especiallyhazardous. The prolonged or_continual_use of aspirin tancause anemia as well_as irri- tate the- stomach lining. AbUse of laxatives or_diuretics_tan_ lead_to a_functional_dependency along_with_potential_dehydratibh or_mineral_defidenties. Use of_antacids.in conjunction With cardiac meditation inhibits effectiveness_of both MeditatienS. The remedy or preventative mostelderly_believe to be harmless is vitamins. However, overuse -or inappropriate to adverSe-reactions. use can lead In generali_it is important to notethat most Pinellas elderly have_directazcess to Medications that can cause symptoms simulating those of Other elderly. diseases of the The real danger- arises when theSesymptoms are treated as unrelated to the over-the-counterMedications is use.

41391_of_the_participantt inditatedno over-the-counter drugs_ currently on hand; An additiehal 39.5% had between 1_ to 3 different medications onhand. 44,RIT those- surveyed possessed_4_or more different over- the- counter medications: "Risk'_!_has been operatienallydefined as possessing 4 or more different over-the-tounter drugsconcurrentlyi_Keep in mind that along with the 4-h616 ofthe elderly_who_have 4_or more over-the-counter drugs on hanc, 19.4% revealedthattheyAlSO

27-436 0 - 84 - 16 238

haVe 4 or more different prescriptionmedications

FIGURE 8

QUANTITY OF OVER-THE-COUNTER DRUGS ON HAND

-f

NONE 67 18;9 1,3_ 140 -39-5 _ F+4 rtm 136:21 18!42 0:4.9' k5tJ11 a TOTAL 354 100.0%

Prescription medicine incombination_with_over-the-counter drugs can yield dangerous results.Previous information indicates that the elderly engage in av--iety_of selfmedicating with- over -the- behaviors.. The risk of experiencing- pboblems counter medication taken in combinationwith prescription drugs increases as the frequency of eachvariable increases. data for the_vari- _ It -is important_to_review the summary ablet Of "number of_prescriptions onhand at home"_and the- on-hand at home" "number ofdifferent over 7the-counter_drugs variables indiVidUally% However; - cross- classification of the two pro'ides a more -in depth view_of_thepotential risk the elderly face daily in their medicine cabinet.

The quantity Of prescriptionmedicine on hand was ploted in relation to the number ofdifferent over,the-counter drugs readily available to each respondent. It- should be_noted that these_ variables ask for current informationregarding the a- vailability of medicine.

Risk levels were_establishedbased upon-the assumption_ that the risk of_mismedicatioh_orincompatiable_combinations increases in relation to_the quantityof prescribed and over- the counter medicines available.

LeVel Definition "n6 risk" "0" prescriptions and "0" over-the-counter drugs on hand "0" prescriptions on hand "low risk" and "1-3" over-the-counter drugs on hand or "1-2" prescriptions on hand and "0-3" over-the-counter drugs on hand

242 239

Level Defiettiee "moderate risk" ."3-6", prescriptions on hand,,_ "4 -6" over-the-counter drugs.:' on hand "high risk" "7" or more prescriptions on ' hand_aid_"7"_or_more over- the counter-drugs on hand.

Data was reviewedon,the congregate,and daircar'e iestiondent?:.'; as a group and' the "at large".`subgroUpseparitelY.Based upon the information available, the .at,large group subgroup ilemOn- strated significantly :hi gher ri sly, than the congregate /day" care group ."- 70:6% of the at '.large sebgroup., cited a risk 1 evo1 .of moderate to- _In comparisefii- the day ,carejcongievte .subgrciup identified_ 54 .13%, n',,the_moderetelo, hi g1range,Overalls58 2 of the respo7idelits_indicated_v'rittleval from moderate to Cross-classification inforiation airatlable in'Figures 10: Figure Cross' Classification, Quantity:. of PreScrifti Ok; Drugs on,,Hand Quantity of Over-The-CoUnter-Drugi on Hand Congregate and-Alay !Ca re SebdroUpg

Of OverTire -Winiter-Diliiiki it Of Different__ . Prescriptions on Hand

HONE 1 -2 Prescriptions 3-4 Prescriptions 5-6 Prescriptions 7;9 Prescriptions 10 or More

Total

No Risk: 4.8% Low Risk: 40.9% Moderate Risk:42.8% High Risk: 11.5% Figure 10

Crost Classificatidn _ Quantity Of Prostription Drugs on sand .by Quantity of OverThe Counter Drugs on Hand At Large Subgroup

t-Of Different Prescriptions on Hand NONE I-2 Prescriptions 3-4 Pres cri pti ons 5:6 Prescriptions 7-9 Prescriptions 10 or More

Total 111111 11111

No Risk: 2.3%

Loft Risk: 27.1% , Moderate Risk: '50.6% High Risk: 20.0% - _From_the_informationL:provided it appears as though Pinellas County- elderly have access -to- considerable amountsof prescriptions as Nell -as over-the ,counter_drugsi'thatthey_engagein self.-- diagnostic and_medication_behavlors with_ia moderate amount of .- knOWledge of the potential_sidedffects of themedications used This information suggests that:theelderly are at somerisk of medication misuse. - IV. ilns-a-feMed-feati-on Behaviors . _ Several factors explored in the surveycan_be_considered unsafe medication practices. The following behaviors are considered unsafe: *discontinuance of medication if feeling better *saving old/leftover medication for future use 241

*phoning the doctor for d prescription instead of a visit *when sick engaging in a self diagnostic/medication practi ce -buying something_from_the_store -use of an old- prescription -borrowing medicine_from a friend

-use of a_home remedy _ *using over-the-counter and presceibed medicioes_concur- rently with little or no consultation with t,ho doctor *missed taking prescriptions

**this behavior is not assessed in the short survey administered at the "Senior Citizens Showcase of Services".

Information was available on the prevalence of each unsafe medication behavior. Figure 11 provides a rank order review of the_percentage_involvement of participants with the various unsafe practices; The_most_frequently cited unsafe_practice_was the concurrent use_of over-the-counter drugs_and_prescription medication with little or no consultation with the physician; Self diagnosis /medication ranked second for -the congregate and day care groups.The behavior ranked second for the_at_large group was missing a-prescription.-Of the_unsafe medicating behaviors, the least frequently cited was discontinued use if the participant perceived relief.

Figure 11

Unsafe_Medication_Practices CorTregiste Day Carc AtLarge Overall using_over_the_counter and_prescription_drugs 69.4% 71.4% 74.6% 70.0% without consulting a doctor

Self diagnosis/ 77;6% 69;2% N/A 57;5% medicating

phoned doctor for 41.9% 35.6% 50.6% 42;9% prescription missed prescription 40.0% 17.5% 65.2% 41.6%

failed to discard old 38.9% 32.3% 33.3% 36.3% medications

discontinued prescription 22.4% 12.0% 25.4% 21.3% if feeling better

Previously_each_behavior_was_reviewed independently. How- ever; the potential deleterious impact is_compounded when participants responses are reviewed to identify_their_total_involve, ment in- unsafe behaviors. Information regarding_unsafe_practices was available on all-subgroups. The "atlarge" group was not questioned about self - diagnostic /medicating behaviors; Therefore; 242

the at large group had a maximum-score of 5 for_unsafe behaviors as oppossed to a maximum score of 6 for the congregateand day care groups. Results indicate that_overall 83.1% of-the participants_____ identified_ involvement in at least one unsafe medicationpractice; Additionally; it is of value_to_review the extent of- respondent' - -s involvement with unsafe_medication_oractices. An index-Of Unsafe medication-behaviors ranged from_no_involvement to_involvemeht in -all 6 (5 .10-At large_respondents)_behaviors.__ Operational definitieht include: _1)10W involvement witti_only one_unsafe behavior; 2)moderate involvement with_2T4_unsafe_behaviors;and 3) high involvement With 5 -6 unsafe behaviors: _It_is_important to realize that_the_MOderate range by no means_implies"normal"_ behavior. Themoderate Category accounts for 33%_to_67%_involve- ment with the unsafe behaviors cited. Figure 12_displays_the unsafe_medication practice multiple involvement index. The_ , highest concentration of responses was in the moderate_range;__It is_interesting to note that almost 10% of the congregate _respon- dents_exhibited a high level of involvement in unsafe Medica- tion practices; Figure 12 Rate of InVolvement in Unsafe Medication Practices All Groups

Level of Immlyement Congregate Day Care At Large Total / I % # % I % 60 16.9 No 0 34 16.6 11 17.0 15 17.6 95 26;8 LQW 1 52 25.4 24 36.9 19 22.4 Moderate 2-4 99 48.3 28 43.1 48 56.5 175 49.3 7.0 High 5-6 20 9;7 2 1.0 3 3.5 25 Tbtal 205 100;0 65 100.0 85100.0 355100.0

V. At Risk-ndicatort Available research continually cites thedisproportionate_ inyolvement of the elderly in the useof-medication._Additional informatiam is available upon the variables -and extentof_such use. A concern among elderly service providers is -howsummary___ information on elderly drug use can be translated into anat risk indicator for the target population. Throughout the survey;_participants_were askedquestions Whose subject matter dealt primarily with_risk. There are 11 such questions in the general survey and 9 in theabbreviated 243

version completed at the-Senior Showcase of. Services. An "at risk" index can be established using these factors. The variables that comprise the risk index are as follows: Question Variable Corresponding to Variable tong' Living alone 2 2 Taking 2 or more prescriptions _6 5 Medicating more than_Once a_day 14 7 More than 2 prescriptions at home 17 N/A Unaware_of_side effects 19 6 Missed medication due to forgetfulness 25 _9 Missed_ medication but remedicated upon discovery 26 10 More than 3_over-the-counter drugs at home 31 20 Medicines similar in shape or color 29 19 Unable to read labels 34 17_ .Unable to distinguish between medicines 35 -N/A --. --- Maximum Risk Score 11 9

The various "at risk" factors have been grouped into four levels. The limits of the risk levels are as follows:

tow Risk 1-2 risk factors Moderate -Risk 3-5 risk factors Higff Risk 6-9 risk factors Extremely High Risk 10-12 risk factors* *not available on "at large" respondents

Figure 14 "At Risk" Levels

Level of Involvement Congregate Day Care At Large Toter

% 1- it I No Risk 5 2.4 6 9.2 3 3.5 14 3.9 Low Risk 81 39.5 18 27.7 41 48.2 140 39.4 Moderate Risk 95 46.4 34 52.3 38 44.8 167 47.0 High Risk 23 11.2 7 10.8 3 3.5 33 9.3

Extremely High Risk 1 .5 0 0 N/A N/A 1 .3

24' 244

Overall; 96.1% of the respondents cited at least one "at ilsk"_factor. -Approximately, -47% of all participants cited a risk level in the moderate_range.For program development purposes, those-citing low risk values, 39.4% overall, are an appropriate target group for education-an prevention strategies. The moderate through extremely_high_range prgsent an opportunity ftir intervention and- educationefforts._ Since over 881t of the respondents cited risk levelsof_moderate and, beyonT;there appears to be a significant population that would benefit from elder ed services.

VI. Discussion Question -by question comparison of results of the initial _ elder-med survey and the present instrument are not possible. Questions were reworded_for_greater clarity. However, there are questions -that are comparable._ The initial survey cited 761 prescription use -as compared_to_68.4% in the current 5amp12. Thit difference -is reflective of the current study group ex- hibiting 49.1% involvement with over-the-counter Medications. The reliance and prevalence of over-the-counterdrugs in the 1983 group is highlighted whenreviewing unsafe medication by practices. The major unsafe medication practice reported respondents in the initial survey was toskip_prescribed medi- and cations. Although this behavior may interrupt_ treatment forestall recovery, it is not as-potentiallydangerous_as the practice of taking prescribed medications-along- with over-the- counter dmits without the doctor'sknowledge. The latter -was cited in the 1983 -study as the mostprevalent-unsafe practice. This practice could lead to theconsumption of medications that could be contreAdicatd and produce serious side effects.

The results of the 1983 elder-med survey indicatethe following:

population 1. A large percentage (68.4 %) of the_elderly resident are consuners Of prescription medicine.

prescription 2. Pinellas County elderly_are_not__only consumers of medicine, but almost half (49.1%) of the populationindicate use of over-the-countermedrEgi

44.5% of the elderly population frequently use over-the - counter medication in conjunction with prescribed medicines with little or no consultation with their doctor.

in at least 4. Approximately 83;1% of the elderly population engage one unsafe medication practice. to high 6. Over-half (56.3%) of -the population indicated moderate levels of 6767Vement in unsafe medication practices.

to the 6. The risk of a medication error is increased in relation total number of risk factors that can be ascribedto a respon- fell in dent. Almost In of the survey respondents' risk_scores the high range. An additional 47% cited a moderate risk level.

248 245

7. Finally the data suggest that the majority of the elderly_engage in unsafe medication behaviors and are "at risk" of medication mismanagement.

VII. Summary/Conclusion

Given the involvement_of youth_in_drug use_andmisuse throughout the United_States_i_it is not surprising that research and program development are_geared_toward a younger target population.Available data suggest that_the_elderly while disproportidnately consune prescription andover- the-counter drugs in- relation to their representation in the general population, -are -at a_higher risk of potential misuse of these substances. Operation PAR, Inc. is- committed to prevention, education and intervention strategies for drug and substance abuse for all age levels .

The objective of the elder-med study was to identify and synthesize information on the use and misuse of prescriptimand_over-She counter drugs_among_the_elderly;__Study results indicate that a concern for the high_rate_of medication use and mismanagement -among the elderly is warranted; _Underreporting is common to all age groups on sensitive subjects and is -an expected reaction in self- report inquiries. Jhus,_the_true_dimensions of the drug use/ misuse practices of the Pinellas County elderly may only be estimated from the data.

However, the elder-med survey results serve to reinforce the need fop; medication management services for the elderly. Education and prevention efforts should be concentrated on the dynamics of medication use/misuse in relation to the aging process.__Another_area for_service_development_would_be_to_make the general_population_sensitive_to_the_potential_dangers of dealing with_the aged through medication; Pinellas County elderly_are "at risk" with respect to medication use/misuse, although -the risk can be managed through the delivery of elder- med services. 246

TOTAL CONGREGATE DAY-CARE_ AT LARGE

% _ I % I % I

Sources of In- formation on 00er-The- Counter Medi- cine: 18.3 22.9 5 11.9 11 13:4 49 Advertising 33 11.6 13.2 4 9:5 8 9.8 31 Friends__ 19 -5.2 -3 _2:1 4 9.5 7 8.6 14 Relatives 55 20;5 25 17.4 8 19.1 22 26.8 Pharmacists 8:5 24 9.0 15 10.4 2 -4.8 -7 LAWS- 32.9 95 35,4 49 34.0 19 45_:2 27 Doctors 82 100% 268 100% Total 144 100% 42 100%

Over-The- Counter Medi- cine Currently on Hand at Home

Aspirin/Buf- 27.2 288 25.9 ferin 151 24.5 43 29.4 94 8.2 35 10.1 105 9:5 Antacids 58 9:4 12 Laxatives/ .; 14.1 181 16.3 105 17.0 27 18:5 49 Diuretics 2.9 39 3.5 26 4.2 3 2.1 10 Iron Pills -.9 21 1.9 15 2:4 3 2.1 3 Mineral Oil 81 7.3 49 7.9 9 -6.2 23 6:6 Cold Medicine_ B.4 98 8.8 52 8.4 17 11.6 29 Cough Medicine 6.1 48 4.3 20 3.2 7 4.8 21 Nasal Spray -3.2 -35 3:2 20 3:2 _4 2.7 11 Sleeping Pills 16:8 173 1546 94 15.2 21 14.4 58 VitaminS 3,7 41 3.7 Other 28 4.6 -13 100% 346 100% 1,110 100% Total 618 4.6 146

7- 20 0 ,1. 247

CONGREGATE DAY CARE AT LARGE TOTAL Number Of Different Over-The-Counter % I 1 % Medicine On Hand At None!

NONE 42 20;5 20 31.3 5 5.9 67 18;9 1 23 11.2 10 15.6. -8 -9.4 41 11.6 2 32 15.6 7 10.9 10 11.8 49 13.2 3 23 11.2 11 17.2 16 18.8 50 14;1 4 35 17.1 7 10.9 11 12.9 53 15;0 5 19 9;3 4 6;3 14 16.5 37 10.5 6 14 6.8 5 7;8 7 13.2 26 7.3 7 6 2.9 ------6 7.1 12 3.4 8 6 2.9 ---- 5 5.9 11 3.1 9 2 1 ------3 3.5 5 1.4 10 1 .5 ,------1 11 --- . 3 ------, --- 12 ___2 1 _-, ------2 .6 TOTAL 205 100 64 100 85 100 354

Experienced Trouble With Packaging Of Meditine: i

YES 58 36.3 12 24. 42 52.5 112 36;6 NO 102 63.7 38 76; 38 47.5 178 61.4' TOTAL 160 50 80 290 100

251 248

CONGREGATE DAY CANF AT LARGE TOTAL Medicine is Kept: 0 % 0 t 0 t 0

Bathroom 93 49:5 22 35:5 ------lir 46 Kitchen 53 28.2 21 33.9 - 74 29;6 Bedroom 29 15.4 15 24.2 ------44 17.6 Other 13 6.9 4 --- 17 6.8

TOTAL 188 62 ------250

Are Any Medicines Similar in Color/ Shape:

YES -23 18.7 15 29.4 18 27.7 -56 23.4 NO 100 81;3 36 70:6 47 72;3 183 76:6

TOTAL 123 51 65 100 239 100

Able To Read Labels/ Instructions:

Never 15 8:3 8 14:6 2 2;8 25 8:1 Sometimes 27 14.9 13 23.6 16 21.9 56 18.1 Always 139 76.8 34 61.8 55 75.3 228 73.8

TOTAL 181 55 73 309

Difficult to_ Distioquish_Ono Medicine From Another:

Never 111 68:9 34 59:7 ------145 66.5 Sometimes 37 23 15 26.3 ... ---- 52 23.9 Always 13 8.1 8 14.0 ------21 9.6

TOTAL 161 57 100 ------218 249

CONGREGATE DAY CARE AT LARGE TOTAL

0 % 0 % 0 %

Sex:

Mile 102 49;5 16 246 24 28:2 142 39.9 Female 104 _50.5 49 _75.4 61 -71.8 214 60.1 Total 206 100% 65 100% 85 100% 356 100%

LiViii§ Arrangements:

Alone 116 56.6 25 38.5 28 34.6 169 48.1 w/spouse 59 28.9 -8 12.3 52 64.2 119 33.9 w/family_ 20 9:7 25 38:5 1 1;2 46 13.1 w/friends 7 3.4 3 4.6 10 2;9 Group Care 3 1.4 4 6.1 7 2.0 Total 205 100% 65 100% 81 100% 351 100%

Age:

60-69 60 30.0 15 23.8 44 53.0 119 34.4 70-79 85 42:5 19 30.2 32 38;6 136 39.3 80 and over 55 27.5 29 46.0 _7 _8.4 _91 26:3 Total 200 10Q% 63 100% 83 100% 346 100% Fihandal: ;

Social Sec. 190 70.6 55 69.6 70 72.2 315 70.9 Pension 60 22.3 6 7.6 27 27.8 93 20.9 food_Stamps 10 3J 7 8-.9 17 3.8 Welfare 4 1.5 6 7;6 10 2:2 Other Assist. 5 1.9 5 6.3 10 2.2

Total 269 100% 79 100% 97 10Q% 445 100% Multiple financial Sources 55 16 21 _92

. .

253 250

CONGREGATE DAY CARE AT LARGE TOTAL

Under Doctor's Care:

YOS 129 63;8 48 76:2 - - 177 66;8 No 73 36.2 15 23.8 - - 88 32.2 Total 202 100% 63 100% 265 100%

Suffer From:

Colds 73. 14.1 26 15.0 99 14.7 Flu 28 5.4 10 5.8 38 5.7 Headaches 36 6;9 12 6:9 48 7;1 Coughs 39 7.5 12 6.9 51 7.6

Stomach Prob. 31 6.0 8 4.6 39 . 5.8 Arthritis 89 17.2 28 16.2 117 17.4 High Blnod _Pressure_ - -__ 68 13.1 23 13.3 91 13.6 Gas/Indigestion 44 12.3 17 9.9 61 9.1 Leg Cramps 69 13.3 28 16.2 97 14.4 Chest Pain -22 4-;2 -9 _5;2 _31 _4_;6 Total 499 100% 173 10n 672 100% Multiple _Complaints: 1 3/ 17.9 8 12.3 45 16.6 2 32 15.5 10 15.4 42 15.5 3 27 13.1 10 15.4 37 13.6 4 17 tL2 9 13;9 26 9;6 5 14 6;8 4 6.2 18 6.6 6 9 4.4 4 6.2 13. 4.8 7 7 3.4 2 3.0 9 3.3 8 3 1.5 2 3;0 5 1;9 9 3 1;5 1 1.5 4 1.5 10 1 .5 1 .4 0 56 27-,2 15 -23,1 -71 -26,2 Total 206 100% 65 100% 271 100% 251

CONGREGATE DAY CARE AT LARGE TOTAL -

I S P 1 S I t

Description of General Health:

Poor 9 _4;3 5 7.9 14 -5.2 Fair 74 35.8 25 39.7 _99 36:6 Good-- 104 50.2 28 44.5 132 48.9 Excelleqt _20 --9,7 -5 . 7.9 -25 9.3 Total 207 100% 63 100% 270 100% Frequency of Doctor's Visit:

Once_amonth 36 19.3 16 25.9 52 21.D Twice a year 71 38.2 11 17.7 82 33.0 Once -a year 40 21.5 11 17.7 51 20.6 Other 39 21,0 24 311.7. -63 -25,4 Total 186 100% 62 100% 248 100% Sick Days in Past 2 Months:

/Days 552 109 661 4Respondents 158 34 192 Average 3:5 3:2 3;4

Taking Prescribed Medicine:

Yes 129 65.5 46 78.0 175 68:4 No -68 34.5 13 22.0 81 31.6 Total 197 100% 59 100% 256 IOC%

_ :2S5 252

CONGREGATE DAY CARE AT LARGE -TOTAL

% 0 % a % 1 % P

Number of_Pre- Serib0d_Medi- cine$ Being Taken: 62J3 1-2 113 69.3 22 46.8 41 55.4 176 35:1 74 26:0 3 -4 27 16.6 21 44.7 26 5-5 9 55 4 8:5 4 5.4 17 6.0 2.8 7-9 5 3:1 3 4.1 8 10_Or more 9 5.5 , -9 3-.2 100% Total 163 100% 47 100% 74 100% 284

Times Medicated Daily:

62 41.3 15 27:8 21 34.4 98 37.7 1 67 25.8 2 40 26:7 15 27.8 12 19.7 24.6 57 21.9 3 26 17.3 16 29.6 15 19.7 32 12:3 4 17 11.3 3 5.5 12 More -5 3,4 1 _1;6 _fl 2.3 100% Total 150 100% 49 100% 61 100% 260

Quite Taking Medicine if Feeling Better: _61 21.3 Yes 39 22.4 6 12 16 25:4 78.7 No 135 -77.6 44 88 47 .74.6 226 50 100% 63 100% 287 100% Total 174 100% 253

DAY CARE AT LARGE TOTAL

I % 1 t %

Disposition of Leftover Medi- tint:

Save for Late 52 36.1 13 28.3 23 33.3 _88 Throw Out 88 61;1 34.0 31 67.4 46 66.7. 165 63.7 Sha-re 4 2.8 2 4.3 -6 2.3 Total 134 100% 45 100% 69 100% 259. 100% Hunter of Cifferen PrescriptiOns on liandToday:

1-3 123 69-.9 38 67.8 4-6 161 69.4 24 13.6 8 14.3 7-9 32 '13.8 8 4.6 2 3.6 10 10 or more 3 1.7 4.3 0 _3 :1.3 18 10;2 -8 _14.3 .26 Totil 176 100% 11;2 56 In% 232 100% Phoned Doctor For Prescrip- tion:

Yes 77 41.9 21 35.6 40 50.6 138 42.9 No 107 58.1 38 64.4 39 -49.4 184 57.1 Total 184 100% 159 100% 79 100% 322 100% Aware of Medi- cine Side Ef- fects:

Yes 109 72.7 26 48.1 49 650 184 No 41 65.9 273 28 -51=9 26 -340 95 Total 150 1001 34.1 54 100% 75 100% 279 100%

257

rm. 27-436 0 - 84 - 17 254

CONGREGATE DAY CARE AT LARGE TOTAL

0 0 % I 1 0 %

When Sick and_ Did Not Go to the Doctor, I:

Buy_Something from Store 32 20.1 7. 15.6 39 19.1 Use Old Pre- -scription 17 10.7 7 15.6 24 11.B Borrow_from Friends 1 .6 1 .5 Use Home Remedy 29 18.3 2 4.4 31 15.2 Talk -to Pher- _macist 17 10;7 2 4A 19 ' 9;3

Phone Doctor . for Prescrip- -tion 17 10.7 _5 11;1 22 10.8 Nothing _46 25.5 22 _48;9 _68 31,3 Total 159 100% 45 100% 204 100%

Uie Vier The counter Medi- cine:

Yes 84 48 27 52;9 III 49;1 No 91 52 24 _47.1 115 50_;9 Total 175 100% 51 . 100% 226 100%

Use Over The Counter_H/Pre- scriptions:

Yes All 44.3 25 415 35 44;3 141 44;5 NO 102 517 30 _54;5 44 15;7 176 515 Total 183 100% 55 100% 79 100% 317 100% 255

CONGREGATE DAY CARE AT LARGE TOTAL

% P % % 0 %

Constlt Doctor When Using Over-The- Coont_er Medi- ation:

Never 61 41.5 21 42.8 25 39;7 107 Sometimes 41 41.3 27.9 14 28.6 22 34.9 77 29;7 Always 45 30.6 '14 -28.6 16 -25.4 75 -29_ Total 147 100% 49 100% 63 100% 259 100% Missed- Taking- Prescription:

Yet 64 40 1D 17.5 45 No 65;2 119 41.6 -96 60- 47 -82.5 24 34.8 167 Total 160 100% 57 _58_-.4 100% 69 100% 286 100% Reasons for Nftsing_Pi-o- scription:

Felt Better 18 17.3 6 28.6 _3 5;9 -27 15.3 Forgot Q6 63.5 12 57.1 40 78.4 118 67;1 felt_Worxe _ 3 2.9 2 9.5 3 5.9 Did Not Help 8 4;6 9 8.6 1 4.8 2 3.9 Other 12 6.0 8 -7.7 3 5,9 -11 6.2 'fet81 104 100% 21 100% 51 100% 176 100% Response to Missed-Pre- scription: Take another pill 11 12.8 3 14.3 6 13;7 20 Wait -Until 13.2 Next Time 68 79.1 17 80.9 28 63.6 113 74.8 Other _7 8.1 _1 4,8 10 -22,7 18 .12. Total 86 100% 21 100% 44 100% 151 100%

it 29 256

CORGREGATF DAY CARE AT LARGE TOTAL

Cost Of Medicine A % f % f % f % Nardthipt 0

-- -- _87 40.3 YES, 66 41.5 21 36.8 --- 129 59.7 NO 93 58.5 36 63.2 ------,-. 217 100 TOTAL 159 100 57 100 ------

Monthly Medical Expense: 3694 Dollars 3124 :570 --T --147 N 119_ 28 --- Average $26.25 $20.36 - -- 525;13

Unsafe Medicaden Practices .

52 25;4 24 36.9 19 22.4 95 26.8 1 21.7 2 44 21.5 15 23.1 18 21.2 77. 22;4 63 171 3 34 16.6 10 15.4 19 12.9 35 9.8 4 21 10.2 3 4.6 11 3 3.5 16 4.5 5 12 5.8 1 1.5 -N/A -9 -2.5 6 8 _3.9 1 1.5 N/A 17.6 60 161 0 34 16.6 11 17.D 15 .- i--- 100 355 100 TOTAL 205 100 65 100 85 257

CONGREGATE DAY CARE AT LARGE TOTAL Number Of Rik Factors__ Indicated

1 33 16.1 5 7.7 16 18.8 54 15.2 2 48 23.4 13 20 25 29.4 86 24.2 3 49 23.9 10 15.4 20 23.5 79 22.3 4 27 13.2 14 21.5. 11 12.9 52 14.7 5 19 9.3 10 15.4 7 8.2 36 10.1 6 13 6.3 3 4.6 3 3.6 19 5.4 7 8 3.9 2 3.1 -I9 2.4 8 2 1 2 3.1 4 LI .--- .- 9 ------.3 10 1 .5 - -- .3 II ------. ------1z------.-.. ------0 5 2.4 6 9.2 3 3.6 14 3,9 TOTAL 2p5 100 65 100 85 100 355 100 258

. APPENDIX 8 Completion Percentages For Survey Questions

NUMber_Of Nunber_OE Question N Responses 8 Question N Responses 8

I 356 356 .400 19 271 204 75.3 2 356 351 98.6 20' 271 226 83.4 3 356 346 97.2 21 356 317 89.0

, 4 356 353 95,1 22 356 259 72,B 5 356 265 74.4 23 356 286 80;3 6 156 271 76.1 24 .------7 271 271 100 25 --- *------8 271 270 99,6 26 356 268 75,3 _9 171 248 91;5, 27 --- -7- - - -- 10 ------28 ------11 271. 256- 94/5 29 356 290 , 81.5 12 356 284 Mg 30 271 250 92,3 13 356 260 73 31 356 239 67;I 14 356 287 80.6 32 556 309 86.8 15 356 259 72.8 33 271 218 80.4 16 271 232 85.6 34 271 216 79.7 17 356 322 90,4 35 ------18 356 279 78.4 ------

. .

22 APPENDIX

16/21/83 CAUSE'EFFECT RELATIONSHIP BETWEEi EACH DRUG AND REACTION PAGE 59 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL__ OCCURRENCES

BODY AS A WHOLE

COSTART COUNT ADRENERG SYND 1

COSTARTCOUNT ALLERO REACT 2

COMP COUNT ANAPHYL

NSTART COUNT ANOMALYCOHEN

COSTART COUNT ANTICHOLINERG SYHD 1

COSTART COUNT ASTHENIA A COSTART COUNT CHILLS

COSTARTCOUNT CHILLS FEVER

COSTA!!COUNT DEATH 1

COSTART COUNT EDEMA FACE 4

COSTART COUNT FEVER 2

COSTART COUNT HEADACHE 7

COSTART COUNT INFECT

COSTART COURT MALAISE

COSTART COUNT OVERDOSE

COSTARTCOUNT OVERDOSE ACCN 3

COSTART COUNT OVERDOSE IKTEtil 1

COSTART COUNT PAIN 1

COSTART COUNT PAIN ABDO 2

COSTAR!COUNT PAIN CHEST

COSTAR! COUNT SERUM SICK 1

COSTAR! COUNT SHOCK 1 01/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN-EACH-DRUON ACTION PAGE 60 CANNOT BE ESTABLISHED WITH CERTAINTY II9L ES

PPA CONTAIPINO ORUOS

AGE COSTART TOTAL OCCURRENCES

BODY AS A WHOLE

AGE COUNT 48

COSTART COUNT 0 hADACHE

COSTART COUNT 0 NO DRUG EFFECT

COSTART COUNT 0 OVERDOSE

AGE COUNT 0

COSTART COUNT 1 ANOMALY CONGEN MULT 1

COSTAIT CUNT I DEATH 1

COSTART COUNT I ECTROMECIA

COSTART COUNT I OVERDOSE ACCID

COSTART COUNT I SERUM SICK

AGE COUNT I 5

COSTART COUNT 2 ALLERO REACT

COSTART COUNT 2 OVERDOSE ACCID

AGE COUNT 2

COSTART COUNT 3 OVERDOSE ACCID

AGE COUNT 3

COSTART COUNT 4 OVERDOSE ACCID 1

"AGE COUNT 4

COSTART 1UNT 7 ASTHENIA 1

AGE COW 7 1

COSTART COUNT 8 ASTHENIA 2 06/21/83 CAUSE-EFFECT RELATIONSUP BETWEEN EACHIRUO_ANKR OION PAGE 61 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL* ES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

BODY AS A WHOLE

AGE COUNT 8

COSTART COUNT 11 ALLEN REACT

AGE COUNT 11

COSTART COUNT 15 EDEMA FACE

AGE COUNT 15 1

COSTART COURT 17 ANAPHYt 1

COSTART COUNT 17 FEVER

AGE COUNT 17 2 cr)

COSTART COUNT 18 OVERDOSE INTENT 2 0

AGE COUNT 18

COSTART COUNT 19 OVERDOSE INTENT

AGE COUNT 19

COSTART COUNT 20 HEADACHE

COSTAR' COUNT 20 OVERDOSE INTENT

COSTART COUNT 20 PAIN 1

AGE COUNT 20 4

COSTART COUNT 22 HEADACHE 1

AGE COUNT 22 1

COSTART COUNT PI OVERDOSE INTENT 1

AGE COUNT 1

COSTART COUNT 24 ECTROIELIA

COSTART COUNT 24 PVERDOSE 1.1 06/21/83 CAOSE.EFFECT RELATIONSHIP 1ETWEEN EICN-DRUO-ANO REACTION PACE 62 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAININO DRUGS

AGE COSTART TOTAL OCCURRENCES

BODY AS A WHOLE

AGE COUNT 24

COSTART COUNT 26 HEADACHE

AGE COUNT 26

COSTART COUNT 27 ANTICNOLINERO SYNC

COSTART COUNT 27 HEADACHE

COSTART COUNT 27 PAIN CHEST

AGE COUNT 77 6

COSTART COUNT 28 ANAPHYL 1

COSTARTCOUNT 28 EDEMA FACE 2

COSTART COUNT 28 HEADACHE

ACE COUNT 28

COSIARTCOUNT 30 ALLERO REACT

COSTARTCOUNT 30 HEADACHE 1

AGE COUNT 30

COSTART COUNT 31 EDEMA FACE

COSTART COUNT 31 INFECT

AGE COUNT 31

-COSTAR! COUNT 32 ANOMALY CONGEN

COSTART COUNT 32 HEADACHE 1

COSTART COUNT SERUM SICK 1

AGE COUNT 32 3 )

r *106/21/83 CAUSE!EFFECT RELATIONSHIP BETWEEN EACH DRUG_ANDRETION PAGE 63 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAININO DRUGS

AGE COSTART TOTAL- OCCURRENCE;

BODY AS A WHOLE

COSTART COUNT 33 AHAPHYL

COSTART COUNT 33 ECTROMELIA

COSTART COUNT 33 EDE"A FACE 1

COSTART 'AUNT 33 HEADACHE

AGE COUNT 33

COSTARTCOUNT 34 ANAPHYL 1

COSTARTCOUNT 34 EDEMA FACE

COSTART COUNT 34 HEADACHE

AGE COUNT 34 3

COSTART COUNT 35 ANAPHYE 2

AGE COUNT 35

COST' T COUNT :6 PAIN CHEST

t AGE COUNT 36

COSTART COUNT 37 SERUM SICK

AGE COUNT 37

COSTARTCOUNT 38 PAIN CHEST

COSTART COUNT 38 WITHDRAW SYqD

AGE COUNT 38 2

COSTART COUNT 43 EDEMA FACE 1

AGE COUNT 43

COSTART COUNT 45 HEADACHE

__AGE COUNT 45 Y67 1.011 i _v 1,

,f kr 1 06/21/83 CAUSE!EFFECT REIITIONSHIP BETWEEN EACH_DRUOAND REACTION PAGE 64 CANNOT BE EScABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAININO DRUGS

40E COSTART TOTAL OCCURRENCES

BODY AS A WHOLE

COSTART COUNT 46 ASTHENIA

AGE COUNT 46

COSTART COUNT 4$ HEADACHE

COSTART COUNT 4$ PAIN

AGE COUNT 08 2

COSTART COUNT 49 EDEMA FACE

AGE COUNT 49

COSTART COUNT 50 OVERDOSE 1

AGE COUNT 50 1

COSTART COUNT 51 PAIN ABDO

COSTART COUNT 51 PAIN CHEST

AGE COUNT 51 2

COSTARTCOUNT 54 SERUM SICK 1

AGE COUNT 54

COSTART COUNT 55 ASTHENIA

COSTART COUNT 55 HEADACHE

COSTART COUNT 55 PAIN CHEST

410E COUNT 55 3.

COSTART COUNT 56 ASTHENIA 1

COSTARTCOUNT 56 CEREBROVASC ACCID

COSTAiT COUNT 56 NO DRUG EFFECT 263 06/2143 CAUSEEFFECT RELATIOW_BETWEEN EACH DRUG_ANkihnION PAGE 65 CANNOT BE ESTABLISHED WITH CERTAINTY IN AlqASE59

Ph CONTAINING DRUGS

AGE COSTART TOTAL__

OCCURRENCES

BODY AS A WHOLE

AGE COUNT 56

COSTART COUNT 58 MALAISE 1

AGE COUNT 58 1

COSTART COUNT 60 HEADACHE 1

AGE COUNT 60 1

COSTAR"! COUNT 62 HEADACHE 1

COSTART COUNT 62 OVERDOSE 1

AGE COUNT 62 2

COSTART COUNT 64 WEADACHE 1

COSTARTCOUNT 64 NO DRUG EFFECT 1

COSTARTCOUNT 64 PAIN

AGE COOP 64 3

COSTART COUNT 74 INFECT 1'

AGE COUNT 74 1

COURT COUNT 85 PAIN ABDO 1

AGE COUNT 85

WART COUNT 88 HEADACHE

COSTART AUNT 88 PAIN CHEST

AGE COUNT 88

COSTARTCOUNT 95 ALLERO REACT 1

AGE COUNT 95 1

OODYCLAS COUNT 138 16/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION PAGE 66 CANNOT SE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART 1DTAL

OCCURRENCES

BODY AS A WHOLE

CARDIOVASCULAR SYSTEM

COSTART COUNT ANGINA PECTORIS 3

COSTART COUNT CEREBROVASC ACCID

COSTART COUNT HEAPT ARREST 2

MINT NOR KYPZRTENS

COSTART COUNT MIGRAINE 2

COSTART COUNT PALPITAT

COURT COUNT PERICARDITIS 1

COSTART COUNT SHOCK 1

COSTART COUNT SYNCOPE

COSTART COUNT VASCULITIS 1

COSTART COUNT VASODILAT

AGE COUNT 22

COSTART COUNT 0 THROM CERESR

AGE COUNT 0

COSTART COUNT 3 VASCULITIS

-AGE COUNT

COSTAR! COUNT 4 HEART ARREST

COSTART COUNT 4 TACHYCARDIA

AGE CDOPT 4

COSTART COW 8 TACHYCARDIA 270 CAUSE.EFFECT RELATIONSHIP BETWEEN EACH DRUG AND RE PAGE 67 06/21/83 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CAS

?PA CONTAININO DRUBS

COSTART TOTAL-- . AGE OCCURRENCES

cARDIOVASCULA1 SYSTEM

AGE COUNT 8 1

COSTARTCOUNT 12 HYPERTENS

COSTARTCOUNT 12 TACHYCARDIA 1

AGE COUNT 12 2

clgTARTCOUNT 13 HYPERTENS

COSTARTCOUNT 13 SYNCOPE

AGE COUNT 13 2

COSTART COUNT 16 SHOCK

ACE COUNT 16

COSTAR! COUNT 19 HEART AM 1

AGE COUNT 19

COSTAR!COUNT 20 HYPERTENS

AGE COUNT 20 2

COSTART COUNT 21 EXTRASYSTRES

COSTART COUNT 21 PALPITAT 2

AGE COUNT 21 3

COSTAR! COUNT 22 HYPERTENS

-AGE COUNT 22

COSTART COUNT 25HYPERTENS COSTART MINT 25NYPOTENS 1 271 COSTART COUNT 25 PALPITAT 2 16/21/13 CAUSEEFFECT RELATIONSHIP_BETWEEN EACH DRUG_AND REACTION PACE 68 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPACONTWING DRUO5

01 CUSTART TOTAL OCCURRENCES

CARDIOVASCULAR SYSTEM

COSTARTCOUNT 25 TACHYCARDIA

AGE COUNT 25

COSTART COUNT 26 HEART ARREST

COSTART COUNT 26 HYPERTENS 2

AGE COUNT 26 3

COSTART COUNT 21 HYPERTENS 2

(05TART COUNT 21 TACHYCARDIA

AGE COUNT 2? 3

COSTARTCOUNT 28 ECO ABNORM

COSTART COUNT 28 INFARCT MYOCARD I

COSTART COUNT 28 SYNCOPE 1

AGE COUNT 28 3

COSTART COUNT 30 ANOMALY HEART 1

ACE COUNT 30

COSTART COUNT 31 HYPERTENS

AGE COUNT 31

CliTART COUNT 32 HEM INTRACRAN

COSTART COUNT 32 HYPERTENS 1

AGE COUNT 32 2

COSTART COUNT 33 HEART ARREST 1

COSTART COUNT 33 HYPERTENS 1 AGE COUNT 33 2 272 O6/2I/83 CAMEFFECT RELATIONSHIP BETWEENEACH DRUG_ANO REACTION PAGE 69 CANNOT BE ESTABLISHED WITHCERTAINTY IN ALL CASES

?PA CONTAINING DUOS

AGE 1:4 COSTART TOTAL

OCCURRENCES 0

CARDIOVASCULAR SYSTEM tO

CHM COUNT 34 1 HTPERTENS

AGE COUNT 34

COSTARTCOUNT 36 MORAINE

AGE COUNT 36

COSTART COUNT 37 PERICARDITIS

' AGE COUNT 37 1

COSTARTCOUNT 38 USURP 1

-AO COURT 38 1

COSTART COUNT 40 HEM INTRACRAN 1

AGE COUNT 40

COSTART COUNT 41 SYNCOPE

AOE COUNT 41

CUSTART COUNT 41 HYPOTEHS POST

AGE COUNT 43

COSTART COUNT 44 HYPERTENS

AGE COUNT 44

COSTART COIHT 46 PALPITAT 1

-COSTART COUNT 46 TACHYCARDIA

AGE COUNT 46 2

CO:TARTCOUNT 47 HEM INTRACRAN I

COSTAR? COUNI 47 MERTENS I 273 PAGE 70 CAUSE.EFFECT RELATIONSHIP BETWEEN -E RL 16/21/83 CANNOT 8E ESTABLISHED WITH CERTA WIN ALLCASES

PPA CONTAINING DRUGS

, AGE COSTART _TOTAL_ OCCURRENCES

CARDIOVASCULAR SYSTEM

2 . AGE COUNT 47

COSTARTCOUNT 48 BRADYCARDIA 1

AGE COUNT 48 1

COSTART COUNT 51 1RADYCARDIA

COSTARTCOUNT 51 ENCEPHALOP HYPERTENS

COSTART COUNT 51 HYPOTENS

AG! COUNT 51 r

COSTART COUNT 53HYPOTENS

COSTART COUNT 53 SYNCOPE 1

AGE COU41 53 2

) COSTART COUNT 55CEREBROVASC ACCID

COSTART COUNT 55SYNCOPE

AGE COUNT 55

COSTART COUNT 56 CEREBROVASC ACCID

2 AGE COUNT 56

COSiART COUNT 58HYPERTENS

AGE COUNT 58

COSTART COUNT 62 ANGINA PECTORIS

1 AGE COUNT 62

COSTART COUNT 63 HYPERTENS 274

AGE COUNT 63

2 :COSTART COUNT 64 SYNCOPE 06/21/83 CAUSFEFFECTRELITIONSHIPIETWEEHEACH-ORUG-ANO-REACTION PAGE 71 CANNOT BE ESTABLISHED WITH CERTAINTY IN Ili ICApS

PPA CONIAININO DRUGS I) )4

AGE COSTAR? TOTAL OCCURRENCES

CARDIOVASCULAR SYSTEM

AGE COUNT 64 2

COSTART COUNT 67 BRADYCAROIA

AGE COUNT 67

COSTART COUNT 61 CEREBROVASC ACCID

AGE COUNT 69 1

COSTARTCOUNT 71 MERTENS

COSTART COUNT 71 TACHYCARDIA 1

AGE COUNT 71

COSTART COUNT 72ARRHYTHMIA

COSTART COUNT 72HYPOTENS

COSTART COUNT 72SYNCOPE 1

AOE COUNT 72 3

COSTART COUNT 73ARRHYTHMIA VENT

AGE COUNT 73 1

COSTART COUNT 80 BRADYCARDIA

COSTART COUNT 80 HYPOTENS

AGE COUNT 80 2

-BODYCLAS COUNT 97

DIGESTIVE SYSTEM

COSTART COUNT IEZOAR

COSTARTCOUNT COMP 16/21/83 CAUSE.EPECT RELATIONSHIP BETWEEN- EACH DRUB. 'REREACTION PAGE 12 CANNOT OE ESTABLISHED WITH CERTAINTY IN ALL CASES

?PA CONTAINING OROS

AGE COSTART TOM OCCURRE4CE5

DIOESTIVE SYSTEM

COSTART COUNT DISCOLOR 100TH 1

COSTART COUNT DRY MOUTH 3

COSTART COUNT OASTRITIS HEM

COSTART COUNT 01 DIS 2

COSTART COUNT GLOSSITIS

COSTAR! COUNT JAUNDICE

COSTART COUNT NAUSEA 6

COSTART COUNT NAUSEA VOMIT 4

COSTART COUNT RECTAL DIS 1

COSTART COUNT STOMATITIS

COSTART COUNT STOMATITIS ULCER

COSTART COUNT TOOTH CARIES

COSTAR! COUNT ULCER DUODEN 18 1

AGE COUNT 27

COSTART COUNT 0 DRY MONTH

COSTAR!COUNT 0 NECRO LIVER

AGE COUNT 0 2

miCOSTART COUNT 1 fiHDICE CHOLESTAT

40E COUNT

COUNT 3 VOMIT COSTART 2 6 AGE COUNT 3 06/21/83 CAUSE-EFFECT RELATIONSHIP RIWIEH.EADO.DROO_A Ill 10N " PAGE 73 CANNOT EE ESTAILISNEDKIN CERTAINTY IN All Am

Rh CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES *IV YI

DIGESTIVE SYSTEM

COSTARTCOUNT 4 NAUSEA 1

AGE COUNT 4

COSTAR!COUNT 6 DISCPIOA TOOTH

AGE COUNT 6

COSTARTCOUNT 7 DYSPNAGIA 2

COSTARTCOUNT 7 JAUNDICE 1

AGE COUNT 7

COSTART COUNT 11 HYPER GUM

AGE COUNT 11

COSTARTCOUNT 15PANCREATITIS

AGE COUNT 13

COSTART COUNT 16 DIARRHEA

COSTAR!COUNT 16 JAUNDICE CHOLESTAT 1

COSTARTCOUNT 16 NAUSEA VOMIT 1

AGE COUNT 16 5

COSTART COUNT 18 EDEMA TONGUE

AGE COUNT II

COSTAR! COUNT 21 VOMIT 1

AGE COUNT 20 1

COSTAR! COUNT 21 LIVER FUNC WORM 1

AGE COUNT 21 1

COSTARTCOUNT 22 PANCREATITIS 277 06 /21 /83 WHIFFET REIATIONSNIP IETWEENI _puip_AND REACTION PAGE 74 CANNOT BE ESTARISNED WITH CERTA; UN'Att CASES

PPA CONTAINAO DRUGS

AGE COSTART IOTA. OCCURRENCES

DIGESTIVE SYSTEM;

AGE COUNT 22

COSTART COUNT' 6 NAUSEA 1

AGE COUNT '5

COSTART COUNT 26 NAUSEA

AGE COUNT 26

COSTARTCOUNT 27 NAUSEA vC;I1T

COSTART COUNT 27 VOMIT

AGE COUNT 21 2

COSTART COUNT 28 JAUNOICE 1

COSTARTCOUNT 28 STOMATITIS 1

AGE COUNT 28 2

COSTART COUNT 29 DRY MOUTH I

AGE COUNT 29

COSTART COUNT 30 DRY Ell 1

AGE COUNT 51 I

COSTART COUNT 59 THIRST 1

AGE COUNT I9

- COSTART COUNT 41 NAUSEA VOMIT

COSTART COUNT 41 VOMIT

AGE COUNT 41

COSTART COUNT 42 HEM 01 06/1/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AOCCOA AITION PAGE 75 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAIN'051 DRUGS

AGE COSTARY TOTAL OCCURRENCES

DIGESTIVE SYSTEM AGE COUNT 42 COSTART COUNT 48 INTEST PER AGE COUNT 48

COSTART COUNT 49 DRY MOUTH 1

COSTART COUNT 49 DYSPEPSIA 1 COSTART COUNT 49 GLOSSITIS COSTART COUNT 49 LIVER FUNC MORN AGE COUNT 49 COSTART COUNT 50 DRY MOUTH

AGE COUNT 50 1

COSTART COUNT 51 70MIT 1

AGE COUNT 51 1 COSTART COUNT 53 DIARRHEA AGE COUNT 53 COSTART COUNT 54 NAUSEA AGE COUNT 54

COSTART COUNT 55DYSPHAGIA 2

AGE COUNT 55 2 COSTART COUNT 58 HEM GI AGE COUNT 58 COSTART COUNT 59 GI DIS -AGE COUNT 59 279 f

HOE 76 06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN EACH DRUG AND-REACTION CANNOT BE ESTABLISHED WITH CERTAINTY IN ILL CASES

PPA CONTAINING DRUGS

AGE Cr4START TOTAL - OCCURRENCES

DIGESTIVE SYSTEM

COSTART COUNT 60 GI DIS

COSTART COUNT 60 SIALADENITIS 1

AGE COUNT 0

COSTART COT 61 JAUNDICE CHOLESTAT 1

COSTARTCOUNT 61 NAUSEA

AGE COUNT GI 2

COSTARTCOUNT 62 INIY MOUTH I

AGE COUNT 62 1

COSTART COUNT 64 NAUSEA 1

;OE COUNT 64

COSTART COUNT 65 NAUSEA VOMIT

AGE rfAT 6) 1

COSTART COUNT 71 CONSTIP 1

COSTARTCOUNT 71 DIARRHEA 1

AGE COUNT 11 2

COSTARTCOUNT 74 NAUSEA VOMIT 1

AGE COUNT 14 1

-,OSTART COUNT 7! VOMIT

AGE COUNT 75

COSTARTCOUNT 84JAUNDICE CHOIESTAT AGE !AUNT 84 20 06'2145 CAUSEIFFECT RELATIONSHIP BETWEENEACH DRUG AND REACTION PAOE 77 CANNOT BE ESTAILINEO WITH CERTAINTYIN ALL CASES

PPA CONTAINING DIOS

AGE COSTART TOTAL OCCURRENCES

DIGESTIVE SYSTEM

COSTART COUNT 85 DIARANEA

COSTART COUNT 85 GASTRITIS

COSTAR?COUNT 85HEM OI

COSTART COUNT 15 HEPATITIS

AGE COUNT 85 4

COSTART COUNT 81 ANOREXIA 2

AGE COUNT 8! 2 ! -t

1'e 4'1__ IODYCLAS COUNT 19 Gt (1.4e Gi ENVIINE S1TEM P

COSTART COUNT ADH INAPPROP I

COSTART COUNT HYPERTHYR I

AGE COUNT 2

COSTARTCOUNT 6 GOITER I

AGE COUNT 6 1

BOOYCLAS COUNT S

HEMIC PHD LYMPHATIC SYSTEM

COSTARTCOUNT AGRANULOCYTOSIS

COSTARYCOUNT ANEMIA APLAST

COSTAT COUNT ANEMIA NEMOL

CCSTAIT COUNT ANEMIA IRON DEFIC

COSTARTCOUNT CYANOSIS 281 A 01

AHD-REACTION 0021/13 CAUSE-EFFECT RELATIONSHIP IFTWEENEACH DRUG CANNOT BE ESTABLISHED WM CERTAINTY IN ALL CASES

PPA CONTAININO DRUGS

AGE COSTART TOTAL__ OCCURRENCES

HEMIC AND LYMPHATIC SYSTEM

COSTART COUNT LEUKOCYTOSIS

COSTART CPU CEOKOPENIA

COSTART COUNT MARROW DEPRESS 1

COSTART COUNT MARROW NYPERPLASIA 1

COSTART COUNT PURPURA

COSTART COUNT PURPURA THROMBOPEN

COSTART COUNT RBC ARUM 1

AGE COUNT 13

COSTART COUNT 1 PURPURA THRO4OPEN 1

AGE COUNT 1

COSTART COUNT 2 1NTRACPAN HYPERTENS

COSTART COUNT 2 LEUWENIA

COSTART COUNT 2 TUOMBOCYTOPENIA

AGE COUNT 2

COSTART COUNT 3 THROMBOCYTOPENIA

AGE COUNT 3

COSTART COUNT 4 THROMBOCYTOPENIA

"RAGE COUNT

COSTART COUNT 16 THROMBOCYTOPENIA 1

AGE COUNT 16 1

1 COSTATIT COUNT 11 CYANDS7: 06/21/03 CADEIFFEG! RELATIONSHIP BETWEEN -EACH DRUG AND REACTION HOE 79 CANNOT DE ESTABLISHED MTh CERTAINTY111 Ali ;ASES r 4 1 P114CONTAINING G''',1 55 "N ''.. iI t' i

V, COST110 -TOTAL _OCCURRENCES I POI .0

NEMIC AND !APO I It M

IOU COUNT

COSTART COUNT 32 ANMA

AGE COUNT 32

COSTART COUNT 35 AORHUIMIDS:1 1

AGE COUN! 35 1

COSTART COUNT 4! ANEPIA APLAST 2

COSTAR! COUNT 41 ECVNTMOST$ 1

AGE COUNT 41

COSTAR!COUNT 49EO5INOPHIL14

COSTART COUNT 49 LEUKOPENIA

AGE COUNT 49

COSTAR! COUNT 50 ANEMIA IRON DEM

AGE COUNT 50

COSTAR!COUNT 55 THROMBOCYTKM

AGE COUNT 55 1

COSTAR! COUNT 62 PUPURA 1

AGE COUNT 62 1

COSTAR! COUNT 66 ANEMIA 1

AGE COUNT 66

COWRY COUNT 69 INIMMIOCTIOPENIA 1

AGE COUNT 69 ',MARTCOUNT 76 PURPURA 283 06/21/83 CAUSE-EFFECT RELATIONSHIP BETW -1AR DRUG- ANC REACTION PAGE 80 CANNOT BE ESTABLISHED WITH E CAINTY IN ALL CASES PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

HEMtC AND LYMPHATIC SYSTEM

41E COUNT 76

COSTARTCOUNT 85 MARROW DEPRESS AGE COUNT 85 BODYCLAS COUNT 38 ;sox METABOLIC AND NUTRITIONAL DISORDERS 3Jet,

COSTART COUNT ANEMIA IRON DEFIC 1

COSTART COUNT CYANOSIS 1

COSTARTCOUNT EDEMA 1

COSTARTCOUNT GLYCOSURIA 1

COSTART COUNT HYPOGLYCEM 1 COSTART COUNT SGOT INC 2

AGE COUNT 7

COSTART COUNT 7 GROWTH RETARD

AGE COUNT 7

COSTART COUNT 11 HYPERUNICEM 1

AGE COUNT 11 1

COSTARTCOUNT 12 GROWTH RETARD 1

AGE COUNT 12 1

COSTART COUNT 13 CREATINE PK INC 1 COSTART COUNT 13 HYPERGLYCEM 1 284 AGE COUNT 13 2 06/21/83 CAUSE'EFFECT REUTIONSHIP-PETWEEN-EACHDr° REACTION HOE 81 CANNOT OE ESTABLISHED EITH CERTAINTY ASES

PPA CONTAININO DRUGS

AGE COSTART ---TOTAL OCCURRENCES

METAIOLIC AND NUTRITIONAL DISORDERS

COSTARr COUNT 15 EDEMA PFRIPm

AGE COUNT 15

COURT COUNT 18 CYANOSIS 1

AGE COUNT 11

COSTART COUNT 20 EDEMA

COSTART COUNT 20 SOOT INC

AGE COUNT 20

COSTART COUNT 22 CIEATINE PK IMC 1

AGE COUNT 22

COSTART COUNT 23 AVONGRIA

AGE COUNT

COSTART COUNT 24

COSTART COUNT 24 or'. 4%%4 1

AGE COUNT 24 3

COSTART COUNT 25KIJ:TE5 MELL

AGE COUNT 25 1

COSTART COUNT 34 ACIDOSIS

COUNT 34

USURY COUNT 38SOOT INC

COSTARTCOUNT 38SGPT INC

AGE COURT 38 2 r,

01/2I183 .,FECT RELATIONSHIP BETWEEN EACH. DRUG AND REACTION oil BC iSTAILISHEO WITH CERTAINTY IN ALL CASES

PPA CONTAININO DRUB

AGE COSTAR! TOTAL-- OCCURRENCES

METABOLIC AC NUTRIIIIINAL DISORDERS

COSTART COUNT 39 THIRST

AGE COUNT 39

COSTAR! COUNT 43 EDEMA

AGE COUNT 43

COSTART COUNT 44 HYPOGLYCEM 1

AGE COUNT 44

COSTART COUNT 46 HYPERKALEM

AGE COUNT 46

COSTART COUNT 41 GOUT

COSTAR! COUNT 48 HYPONATREM

AGE COUNT 4b 2

COSTART COUNT 49 EDEMA PERIPH

COSTAR! COUNT 49 WEIGHT INC

AGE COUNT 49 2

COSTART COUNT 50 ANNA IRON DEFIC

AGE CUNT 50

COSiiii COUNT 68 HYPEROLYCEM / MI5 COSTW ONNT 68 GOT INC e Y far ti AGE oUhl 68

COSTAR! COUNT 84 WEIGHT DEC AGE COUNT 84 286 ;BODYCLASCOUNT 47 I 06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN-EACH DRUG-ANDiREACTION PAGE 83 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALCIASES v,.10 PPA CONTAINING DRUGS \ e(

AGE COSTAR'' TOTAL

OCCURRENCES

METABOLIC AND NUTRITIONAL DISORDERS

MUSCULOSKELETAL SYSTEM

COSTART COUNT ARARAIGIA

COSTART COUNT MYOSITIS

AGE NUNT

COSTARTCOUNT 2 ARTNRAMA

AG! COUNT 2

COSTART COUNT 3 ARTHRITIS

AGE COUNT 3

COSTART COUNT 6 ARTHRITIS

AGE COUNT 6

COSTART COUNT 21 TETANY

AGE COUNT 20

COSTART COUNT 22MYALGIA

AGE COUNT 22 1

COURT COUNT 26TEIANY

AGE COUNT 26

-COI ARTCOUNT 55ARTNRALOIA

COSTARTCOUNT 55ARTHRITIS 1

AGE COUNT 55 2

COSTART COUNT 56 ARTHRALOIA

ACE COUNT 56 PAGE 84 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRU0 AND REACTION 06/21/83 CANNO1 BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CO'tTAININO DRUB

ACE COSTART TOTAL_ OCCURRENCES mrsafam6,4a

MUSCULONELETAL SYSTEM

BODYCLAS COUNT 11

NERVOUS SYSTEM

COSTIIRT COUNT ADRENERG SYND

COSTARTCOUNT AGITATION

COSTART COUNT AMNESIA

COSTARTCOUNT ANOMALY CONCEN CNS

COSTART COUNT ANTICNOLINERO SYND

COSTARTCOUNT CEREIROVASC ACCID 2

COSTARTCOUNT CNS SUNHAT 2

COSTARTCOUNT CONFUS 4

COSTARTCOUNT CONVUIS

COSTARTCOUNT DELUSIPS

COSTART COUNT OM Ir.,

COSTART COUNT E'

COSTART COUNT

COVART COUNT DIZZINErdS

_COSTART COUNT DRUG DEPEND

COSTARTCOUNT DRY MOUTH

COSTARTCOUNT DATION lABIL

COSTARTCOUNT EUPHORIA

COSTAR? COUNT NALLUCIN

06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN EACHRUG AND REACTION PAGE 85 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM co

CONRT COUNT HYPERTENS

COSTART COUNT INSOMNIA

COSTART aUhT MANIC REACT 1

COSTART COUNT NERVOUSNESS 4

COSTART COUNT NEURITIS RETROBULBAR I

COSTART COUNT OCULOGYRIC CRISIS 1

COSTART COUNT PARALYSIS

Ca COSTAPT COURT PARANOID REACT 1 cr!

COSTART COUNT PERSON DIS

COSTART COUNT PSYCHOSIS

COSTART COUNT SCHIZOPHRENIC REACT 1

COSTART COUNT SOMNOLENCE

COSTART COUNT SPEECH DIS 1

COSTART COUNT URIN RETENT 9

COSTART COUNT VASODILAT

COSTART COUNT VERTIGO

AGE COUNT 75

' COSTART COUNT 0 DIZZINESS

COSTART COUNT 0 DRY MOUTH

COSTART COUNT 0 OPISTOOTONOS

COSTART COUNT 0 THRUM CEREBR 289 O6/21/B3 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH-Mr-Mk REACTION PAGE 86 CANNOT BE ESTABLISHED WITH CERTAINTY XALLTASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

AGE COUNT 0

COSTARTCOUNT 1 CONVULS

COSTARTCOUNT 1 CONVULS GRAND MAL 1

COSTARTCOUNT I HYPERKINESIA 1

COSTART COUNT I INSOMNIA

COSTARTCOUNT I INTRACRAN HYPERTENS 2

COSTART COUNT I PERSON DIS

AGE COUNT 1

COSTART COUNT 2 COORDINAT ABNORM 1

COSTART COUNT 2 HALLUCIN

COSTART COUNT 2 HYPERKINESIA

COSTART COUNT 2 INTRACRAN HYPERTENS

COSTART COUNT 2 NERVOUSNESS

COSTART COUNT 2 SOMNOLENCE 1

AGE COUNT 2 11

COSTART COUNT 3 CONVULS GRAND MAL 1

COSTART COUNT 3 HYPERKINESIA 2

_COSTARTCOUNT 3 INSOMNIA 1

COSTART COUNT 3 PERSON DIS

COSTARTCOUNT 3 SOMNOLENCE

AGE COUNT 3

COSTARTCOUNT 4 CNS STIMU1AT tA I

06/21/85 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION PAGE 87 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL._ _ OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 4 EXTRAPYR SYND

COSTARTCOUNT 4 HALLUCIN 2

COSTAR! COUNT 4 HYPERKINESIA 2

COSTART COUNT 4 OCULOGYRIC CRISIS 1

COSTART COUNT 4 SOMNOLENCE 2

AGE COUNT 4 9

("TART COUNT 5 DREAM ABNDRM

COSTAR COUNT 5 MENTAL RETARD

COSTAR! CPT 5 NEUROPATHY 1

AGE OW 5

COSTAR! COVNT 6 HALLUCIN 1

CWIART COUIIT 6 NYPERKINESIA

AGE COUNT 6 2

L;STARI COUNT 1 CONVULS GRAND MAL

CWART COUNT 1 DEPRESSION 1

COSTART COUNT 7 EXTRAPYR SYND

CC51ART COUNT 1 HALLOCIN 1

'COSTAR! COUNT 7 !ERVOUSNESS

AGE OUNT 1 5

CO!TAfl C(11111 8 NERVOUSNESS

ADE 06/21/83 CAUSEbEFFECT RE! TIONSHIP BETWEEris IbRUGAND-REACTION PAGE 88 CANNOT BE ESTABLISHED WITHCERTAINTYIN All CASES

PPA CONIAINING DRUGS

AOE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 11 SOMNOLENCE

AGE COUNT 11 1

COSTART COUNT 12 HYPERTENS 1

AGE COUNT 12 1

a 'ART COUNT 13 CNS STIMUIAT

CO' co' ,' 13 HYPERTENS

CC1H1 13 2

Coy ie 1UNI 14 CON1ULS 2

AGE CO' IT 14

COSTART COUNT 15 SOMNOLENCE

AGE COUNT 15

COSTART COUNT 17 HAillICIN

COSTART COUNT 17 NEMESIA

COSTART COUNT 17 SOMNOLENCE

AGE COUNT 17 4

COSTART COUNT 18 DIZZINESS 2

COSTART COUNT 18 DYSARTHRIA

;COSTART COUNT 18 SOMNOLENCE

COSTART COUNT 18 STUPOR 1

COSTART COUNT 18 TORTICOLLIS 1

AGE COUNT 18

COSTART COUNT 19 SOMNOLENCE 1 06/21/83 CAUSFEFFECT RELATIONSHIP BETWEEN EACH_DRUG_AND REACTION PAGE 89 CANNOT BE ESTABLISHED WITH CERTAINTY1NILL CASES

) PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVO4S SYSTEM

AGE COUNT 19

COSTART COUNT 20 COMA

COSTART COUNT 20 HYPERTENS 2

COSTART COUNT 20 SOMNOLENCE

AGE COUNT 20

COSTART COUNT 22 COORDINAT ABNORM 1

COSTART COUNT 22 DIZZINESS 1

COSTART COUNT 22 HYPERTENS

COSTART COUNT 22 SOMNOLENCE 1

AGE COUNT 22

COSTART COUNT 23 HALLUCIN

COSTARTCOUNT 23 NYSTAGMUS 1

COSTART COUNT 23 SOMNOLENCE 1

COSTART COUNT 23 URIN RETENT 1

AGE COUNT 23 4

COSTART COUNT 24 CONVULS

COSTART COUNT 24 CONVULS GRAND MAL

""COSTART COUNT 24 DEPRESSION

COSTART COUNT 24 NERVOUSNESS

COSTART COUNT 24 SOMNOLENCE

AGE COUNT 24 293 06/21/83 CAOSEFFFECT RELATIONSHIP BETWEEN-EACRADRUGiiHD-REACTION PAGE 90 CANNOT BE ESTABLISHED WITH CERTAINIIK AL CASES

PPA CONTAIN1110 DRUGS V

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 25 ATAXIA

COSTART COUNT 25 CONVULS

COSTART COUNT 25 DIZZINESS

COSTART COUNT 25 HALLUCIN

COSTART COUNT 25 HYPERTENS 1

COSTART COUNT 25 NERVOUSNESS

COSTART COUNT 25 SOMNOLENCE

COSTART COUNT 25 IORTICOLLIS

AGE COUNT 25

COSTART COUNT 26 ANXIETY

COSTART COUNT 26 ATAXIA

COSTART COUNT 26 DIZZINESS 1

COSTART COUNT 26 EMOTION LABIt 1

'COSTART COUNT 26 HEM INTRACRAN 1

COSTART COUNT 26 HYPER' '5 3

COSTART COUNT 26 PARESTHESIA 2

COSTART COUNT 26 SOMNOLENCE 1

-AGE COUNT 26 11

COSTART COUNT 27 ANTICHOLINERG SYND 1

COSTART COUNT 21 HYPERTENS 3

COSTART COUNT 21 NEURITIS PERIPH 1 294 ...AGE COUNT 27 5 06/21/83 CAUSE,EFFECT RELATIONSHIP BETWEEN EACH_DRUG_Ap '610N NE 91 CANNOT BE ESTABLISHED WITH CERTAINTY IN Al'CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 28 DIZZINESS I

COSTART COUNT 28 NYSTAGMUS I

COSART COUNT 28 SOMNOLENCE 2

COSTART COUNT 28 SPEECH DIS

AGE COUNT 28 5

COSTART COUNT 29 COORDINAT ABNORM

COSTART COUNT 29 DEPRESSION

COS1R1 COUNT 29 DRY MOUTH

COSTART COUNT 24 EUPHORIA 1

COSIART COUNT 29 SOMNOLENCE

AGE COUNT 29 5

COSTART COUNT 30 ANXIETY 1

COSTART COUNT 30 CONVULS GRAND MAI 1

COSIART COUNT 30 DIZZINESS 1

COSTART COUNT 30 DRY MOUTH

AGE COUNT 30

COSTART COUNT 31 HYPERTENS 1

meCOSTART COUNT 31 PARESTHESIA 1

COSTART COUNT 31 SOMNOLENCE

AGE COUNT 31 3

COSTART COUNT 32 CONVULS PAGE 92 06/21/83 COSE.EFFECT RELATIONSHIP BETWEEN Egg,govo REACTION CANNOT BE ESTABLISHED WITH CERTAINI/IN ALL CASES

1 .

?PA CONTAINING DRUGS

AGE COSTART TOTAL-- OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 32 HEM INTRACRAN

COSTART COUNT 32 ElPERTENS

COSTART COUNT 32 HYPERTONIA

COSTART COUNT 32 SOMNOLENCE 2

AGE COUNT 32 6

COSTART COUNT 33 HAINC111 I

COSTART COUNT 33 HYPERTENS

COSTART COURT 33 SOMNOLENCE

AGE COUNT 33 3

COSTART :OUNT 34 CONVUlS

COSTART COUNT 34 DIZZINESS

COSTART COUNT 34 HYPERTENS

AGE COUNT 34

COSTART COUNT 35 HALLUCIN

COSTART COUNT 35 SOMNOLENCE 2

AGE COUNT 35

COSTART COU1T 36 HEM INTRACRAN

;COSTART COUNT 36 STUPOR 1

AGE COUNT 36 2

COSTART COUNT 37 ATAXIA

AGE COUNT 31

COSTART COUNT 38 DIZZINESS e)

B6/21/N CAUSE-EFFECT RELATIONSHIP BETWEEN-EACH DRUG-ANT-tiACTION CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART -TOTAL OCCURRENCES

NERVOUS 5,YSTEM

COSTART COUNT 38 DREAM ABNORM

COSTART COUNT 38 DRUG DEPEND 1

COSTART COUNT 38 HYPERTENS

COSTART COUNT 38 VASODILAT

COSTART COUNT 38 WITHDRAW SYNC, 1

AGE COUNT 38

COSTART COUNT 39 SOMNOLENCE

COSTART COUNT 39 URIN RETENT 1

COSTART COUNT 39 VESTIBUL DIS

AGE COUNT 39 3

COSTART COUNT 40 HEM INTRACRAN 1

cASTART COUNT 40 1OMNOLENCE

AGE COOP 40 2

COSTART COUNT 41 SOMNOLENCE 1

COSTART COUNT 41 URIN RETENT 1

AGE COUNT 41 2

COSTART COUNT 42 CONFUS 1

COSTART COUNT 42 COORDIHAT WORM 1

AGE COUNT 42

COSTART COUNT 43 HALLUCIN 297

COSTART COUNT 43 PARES1NESIA PAGE 94 CAUSE-EFFECT RELATIONSHIP BETWEEN-EACHDRUO AND-REACTION 6/21/83 IN ALL CASES CANNOT BE ESTABLISHED WITH CERTAINTY

Ppit CATAINING DRUGS

TOTAL__ AGE COSTART OCCURRENCES

NER4CUS SYSTEM

2 AGE COUNT 45

COSTART COUNT 44 CEREBROVASC DIS

1 COSTAR! COUNT 44 NYPERTENS

AGE COUNT 44

COSTART COUNT 45 HYPERTENS

AGE COUNT 45

COSTART COUNT 46 SOMNOLENCE

AGE CUNT 46

COSTART COUNT 47 HEM INTRACRAN

1 COSTART COUNT 47 NYPERTENS

2 AGE COUNT 47

COSTARTCOUNT 48 BRAIN gNO ACUTE

1 COSTARTCOUNT 46 COMA

COURT COUNT 48 DIZZINESS

COSTARTCOUNT 48 WYPERTENS

AGE COUNT 48

DRY MOUTH COSTARTCOUNT 49

COSTARTCOUNT 49 INTRACRAN HYPERTENS

AGE COUNT 49

DRY MOUTH COSTAR?COUNT 50

COSTARTCOUNT 50 PSYCHOSIS

COSTARTCOUNT 50 SOMNOLENCE 1' 1

16/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION PAGE 95 CANNOT BE ESTABLISHED WITH CERTAINTY IN All CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL-- OCCURRENCES

NERVOUS SYSTEM

AGE COUNT 50

COSTART COUNT 51 DELUSIONS 1

COSTART COUNT 51 MENLO!' NYPERTENS 1

COSTAR' COUNT 51 WHIN 2

AGE COUNT 51 4

COSTART COUNT 52 DIZZINESS

COSTART COUNT 52 SOMNOLENCE 1

AGE COUNT 52 2

COSTART COUNT 53 DIZZINESS 1

AGE COUNT 53 1

COSTART COUNT 55 CEREBROVASC ACCID

COSTART COUNT 55 INSOMNIA 1

COSTAR! COUNT 55 NERVOUSNESS 1

COSTART COUNT 55 URIN RETENT 1

AGE COUNT 55 4

COSTART COUNT 56 CEREBROVASC ACCID 2

COSTAR! COUNT 56 PARALYSIS 2

-AGE COUNT 56 4

COSTART COUNT 57 URIN RETENT

AGE COUNT 57 1

COSTART COUNT 58 HYPERTENS 299 6 A

06/21/85 CAUSE.EFFECT RELATIONSHIP BETWEEN EA011110-ANO REACTION PAGE 96 CANNOT OE ESTABLISHED WITH CERTAINTY IN All CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL

_,-. OCCURRENCES

NERVOUS SYSTEM

AGE COUNT 58

COSTART COUNT 60 DIZZINESS

COSTART COUNT 60 HEMIREGIA

COSTART COUNT 60 HYPERTENS

AGE COUNT 60

COSTART COUNT 61 AMNESIA

COSTART COUNT 61 DIZZINESS

COSTART COUNT 61 SOMNOLENCE

AGE COUNT 61 3

COSTART COUNT 62 DEPRESSION

COSTART COUNT 62 DRY MOUTH

COSTART COUNT 62 URIN RETENT

AGE COUNT 62 3

COSTART COUNT 63 COMA 1

COSTART COUNT 63 HYPERTENS 1

AGE COUNT 63 2

COSTART COUNT 66 CONFOS 1.

;COSIAlt COUNT 66 HOSTILITY 1

COSTART COUNT 66 HYPERTENS 1

COSTART COUNT 66 URIN RETENT

AGE COUNT 66 4

COSTART COUNT 67 SOMNOLENCE 300 D6/2i /b5 CAOSE.EFFECT RELATIONSHIP BETWEEN-EACR 10-REACTION PAGE 97

CANNOT BE ESTABLISHED WITH CERTAINT A CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 67 STUPOR 1

AGE COUNT 67 2

COSTART COUNT 69 CEREBROVASC ACCID 1

AGE COUNT 69

COSTART COUNT 70 BRAIN sYlio ACUTE 1

COSTART COUNT 10 URIN REMIT 1

AGE COUNT 70 2

COSTART COUNT 71 HYPERTENS

COSTAR? COUNT 71 TORTICOLLIS

COSTAR? COUNT 11 TREMOR

AGE COUNT 71 3

COSTART COUNT 15 AMNESIA 1

COSTART COUNT 75 DIZZINESS 1

COSTART COUNT 75 SOMNOLENCE

AGE COUNT 75

COSTAR COUNT 17 URIN REIM

AGE COUNT 77 1

" COSTART COUNT 81 URIN RETENT 1

AGE COUNT 81

COSTART COUNT 88 TREMOR

88 col AGE COUNT 1 16/2143 CAUSE-EFFECT RELATIONSNIVIETWEEN-EACH-DRUG-AND-REACTION PACE 98 CANNOT BE ESTABLISHED WITH CE TAINT; IN All CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

NERVOUS SYSTEM

COSTART COUNT 89 CONNS

1;L

AGE COUNT 89 2 e'

BODYCIAS COUNT 300 (;46

RESPIRATORY SYSTEM

COSTART COUNT ASTHMA 2

COSTART COUNT BRONCHITIS 2

COSTAR! COUNT HICCUP 1

COSTART COUNT LARYNGITIS 1

COSTART COUNT PHARYNGITIS 1

COSTART COUNT PNEUMONIA I

COSTART COUNT RHIHITIS 2

COSTART COUNT SINUSITIS 4

ACE COUNT 14

COSTART COUNT 2 HYPERVENTIL 1

AGE COUNT 2

COSTART COUNT 13 DYSPHEA

AGE COUNT 13

4eCOSTART COUNT 14 DYSPHEA

AGE COUNT 14

COSTART COUNT 16 DYSPHEA 1

AGE COUNT 16

m' 06/21/83 CAUSE-EFF:CT RELATIONSHIP BETWEEN EACH DRUG RUCTION PAGE 99 CANNOT BE ESTABLISHED WITH CERTAINTY IN AL ASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL

OCCURRENCES

RESPIRATORY SYSTEM

COSTART COUNT 18 HYPERVENTIL

COSTART COUNT 18 HYPOVENTIL 1

AGE COUNT 18 2

COSTART COUNT 19 APNEA 1

AGE COUNT 19 1

COSTART COURT 21 APNEA 1

AGE COUNT 21

COSTART COUNT 22 EDEMA ZUNI

AGE COUNT 22

COSTART COUNT 28 PHARYNGITIS

AGE COUNT 28

COSTART COUNT 29 RHINITIS 1

AGE COUNT 29 1

COSTART COUNT 30 ASTHMA 1

COSTART COUNT 30 BRONCHITIS 2

AGE COUNT 30 3

COSTART COUNT 32DYSPNEA

_COSTART COUNT 32 RHINITIS 1

AGE COUNT 32 2

COSTART COUNT 33 HYPERVEHTIL 1

COSTART COUNT 33 RHIHITIS 1

COUNT 33 2 PAGE 100 06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAE

OCCURRENCES 1)

RESPIRATORY SYSTEM

COSTART COUNT 38 DYSPNEA 1

AGE COUNT 38 1

COSTART COUNT 41 EPISTAXIS 1

AGE COUNT 41

COSTARTCOUNT 43 DYSPNEA

AGE COUNT 43

COSTART COUNT 53 EDEMA LUNG

AGE COUNT 53 1

COSTARTCOUNT 55 DYSPNEA 1

AGE COUNT 55 1

COSTARTCOUNT 58 DYSPNEA

COSTARTCOUNT 58 PNEUMONIA

COSTARTCOUNT 58 RHINITIS

. AGE COUNT 58

COSTART COUNT 60 EPISTAXIS

_ AGE COUNT 60 1

COSTART COUNT 63 RHINITIS 1

s'AGE COUNT 63 1

COSTAR? COUNT 67 EPISTAXIS

AGE COUNT 67

COSTART COUNT 10 ASTHMA 304 06/21/63 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUOiAND,OCTION PACE 101 CANNOT BE ESTABLISHED WITH CERTAINTY IN tLIOASES J I PPA CONTAININO ORUOS w

'AGE 0 COSTART TOTAL___ OCCURRENCES

A RESPIRATORY SYSTEM

COSTART COUNT 70 DYiPHEA

AGE COUNT 70 2 op .1

) BODYCLAS COUNT 45

5.4

SKIN AND APPENDAGES

COSTART COUNT ACHE

COSTART COUNT ALOPECIA 3

COSTART COUNT DERM EVER

COSTARTCOUNT ERYTHEMA MULT 3

COSTART COUNT RASH 13

COSTART UHT RASH MAC PAP

COSTART COUNT RASH PUP 1

COSTART COUNT RASH VESIC BULL 2

COSTART COUNT STEVENS JOHNSON SYND 1

COSTARTCOUNT SWEAT 3

COSTART COUNT URTICARIA 6

AGE COUNT 31

COSTART COUNT 0 RASH MAC PAP 1

-AGE COUNT 0 1

COSTART COUNT 1 ERYTHEMA MULT

COSTART COUNT 1 RASH

AGE COUNT 1 2 305 PAGE 102 06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACHDR4?110/RU!TION CANNOT BE ESTABLISHED WITH CERTAINTY III IL OASES

PPA CONTAINING DRUGS

AGE COSTART _TOTAL-- OCCURRENCES

SKIN AND APPENDAGES

COSTART COUNT 2 ERYTHEMA MKT

COSTART COUNT 2 PRURITUS

COSTART COUNT 2 RASH

COSTART COUNT 2 RASH MAC PAP

COSTART COUNT 2 STEVENS JOHNSON SYND

COSTART COUNT 2 URTICARIA

AGE COUNT 2

COSTART COUNT 3 ERYTHEMA MULT

COSTAR! CUNT 3 PRURITUS

COSTAT COUNT 3 RASH MAC PAP

COSTART COUNT 3 RASH PETECH

AGE COUNT 3 4

COSTARTCOUNT 4 ERYTHEMA MOLT

AGE COUNT 4

COSTART COUNT 6 PRURITUS

COSTART COUNT 6 RASH

COSTART COUNT 6 RASH VESIC BULL

COSTAR] COUNT 6 STEVENS JOHNSON SYND

AGE COUNT 6 4

COSTART COUNT 8 SWEAT AGE COUNT 8 30e COSTART COUNT 14 ERYTHEMA MULT 06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN-EACH LUG AHD REACTION PAGE 103 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

SKIN AHD APPENDAGES

COSTART COUNT 14 URTICARIA

AGE COUNT 14

COSTART COUNT 15 RASH

COSTART COUNT 15 URTICARIA

AGE COUNT 15 2

COSTART COUNT 16 ANGIOEDEMA 1

COSTARTCOUNT 16 RASH 1

COSTART COUNT 16 URTICARIA

AGE COUNT 16 3

COSTART COUNT 19 RASH 1

COSTART COUNT 19 URTICARIA 1

AGE COUNT 19 2

COSTART COUNT 21 RASH

COSTART COUNT 21 RASH VESIC BULL

COSTART COUNT 21 URTICARIA 1

AGE COUNT 21

COSTARTCOUNT 22 URTICARIA

smAGE COUNT 22 2

COSTART COUNT 23 EPIDERM HECRO 1

AGE COUNT 23 1

COSTART COUNT 24 RASH 307 06/21/83 CAUSE-EFFECT REUTIONSHIP-BETWEEN-EACH4DRUG-AND-REACTION PAGE 104 CANNOT BE EST/BLISHED WITH CERTAINTYXlial CASES PPA CONTAINING DRUGS _ AGE COSTART TOTAL OCCURRENCES

SKIN AND APPENDAGES COSTART COUNT 24 URTICARIA 2

AGE COUNT 24 3 COSTART COU"T 26 PRURITUS COSTART COUNT 26 RASH MAC PAP

AGE COUNT 26 2

COSTART COUNT 27 RASH 1

COSTART COUNT 27 SWEAT 1

AGE COUNT 27 2

COSTART COUNT 28 RASH 2 COSTART COUNT 28 RASH MAC PAP

COSTART COUNT 28 SKIN DISCOLOR 1 COSTART COUNT 28 URTICARIA 2

AGE COUNT 28 6 COSTART COUNT 29 RASH AGE COUNT 29

COSTART COUNT 30 ERYTHEMA MOLT AGE COUNT 30

COSTART COUNT 31 PRURITUS 1

COSTART COUNT 31 RASH MAC PAP 1 COSTART COUNT 31 URTICARIA 1 308 AGE COUNT 31 3 COSTART COUNT 33 RASH 2 PAGE 105 06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN-EACH DRUG AND-REACTION CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES 1 4

SKIN AND APPENDAGES

COSTART COUNT 33 URTICARIA

AGE COUNT 33 3

COSTART COUNT 34 PRURITUS 1

COSTART COUNT 34 RASH

COSTART COUNT 34 URTICARIA

AGE COUNT 34 3

COSTART COUNT 35 ANGIOEDEMA 1

COSTART COUNT 35 PRURITUS

COSTART COUNT 35 RASH

COSTART COUNT 35 URTICARIA 2

AGE COUNT 35 5

COSTART COUNT 36 RASH MAC PAP 2

AGE COUNT 36

COSTART COUNT 31 ERYTHEMA MULT

COSTART COUNT 37 URTICARIA

AGE COUNT 37

COSTART COUNT 40 ANGIOEDEMA

-AGE COUNT 40

COSTART COUNT 43 RASH

2 . COSTART COUNT 43 URTICARIA

AGE COUNT 43 3

309 0, 40 .Its i

06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

SKIN AND APPENDAGES

COSTART COUNT 44 URTICARIA

AGE COUNT 44 1

COSTART COUNT 45 URTICARIA 1

AGE COUNT 45 1

COSTART COUNT 46 PRURITUS 1

COSTART COUNT 46 RASH MAC PAP 1

COSTART COUNT 46 RASH VESIC BULL 1

AGE COUNT 46 3

COSTART COUNT 48 RASH MAC PAP 1

COSTART COUNT 48 URTICARIA 1

AGE COUNT 48 2

COSTART COUNT 49 NAIL DIS

COSTART COUNT 49 RASH

COSTARTCOUNT 49 URTICARIA 1

AGE COUNT 49 3

COURT COUNT 51 RASH MAC PAP 1

AGE COUNT 51 1

COSTART COUNT 53 ANGIOEDEMA

COSTART COUNT 53 PRURITUS It 310 COSTART COUNT 53 RASH

AGE COUNT 53

COSTART COUNT 55 EPIDERM NECRO 1 06/21/83 CAUSEIFFECT RELATIONSHIP BETWEEN-EACH- -DRUG AND REACTION PAGE IC? CANNOT BE ESTABLISHED WITH CERTAINTYIN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART --TOTAL- __OCCURRENCES

SKIN AND APENDOES

COSTART COUNT 55 RASH MAC PAP

COSTART COUNT 55URTICARIA

AGE COUNT 55

COSTART COUNT 61 NAIL DIS

COSTART COUNT 61 RASH MAC PAP

AGE COUNT 61 2

COSTART COUNT 65ANGIDEDEMA

AGE COUNT 65

COSTART COUNT 67 RASH VESIC BULL 1

AGE COUNT 67

COSTAR! COUNT 69 ANGIOEDEMA

COSTART COUNT 69 PRURITUS 1

COSTART COUNT 69 RASH

'OSTART COUNT 69 URTICARIA 2

AGE COUNT 69

COSTART COUNT 71 RASH

AGE COUNT 71

""COSTART COUNT 72 RASH

AGE COUNT 72 1

COSTART COUNT 75 ERYTHEMA MULT

AGE COUNT 75

311 r'

CAUSE-EFFEr RELATIONSHIP BETWEEN EACH DRUG AND REACTION PAGE 108 0021/13 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

SKIN AND APPENDAGES

BODYClAS COUNT 140

SPECIAL SENSES

COSTART COUNT AMBLYOPIA 2

COSTART COUNT CONJUNCTIVITIS 2

COSTART COUNT CORNEAL LESION

DEAF 1 , COSTART COUNT

COSTART COUNT EYE DIS

COSTART COUNT GLAUCOMA

COSTART COUNT MYDRIASIS

COSTART COUNT PAIN EAR

COSTART COUNT PAIN EYE 4

COSTARTCOUNT RETINAL DEGENERAT

COSTART COUNT TASTE PERVERS 1

COSTART COUNT TINNITUS

COSTART COUNT VISION ABNDRM

COSTART COUNT VISUAL FIELD DEFECT

24 AGE COUNT

"ECOSTART COUNT 0 AMBLYOPIA

AGE COUNT 0 1

COSTART COUNT 3 PUPIL D1S

AGE COUNT 3 06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN EACH DRUG AND REACTION PAGE 109 CANNOT BE ESTABLISHED WITH CERTAINTY IN-AL- CSE3

11 PPA CONTAINING MOOS

AGE COSTART TOTAL OCCURRENCES

SPECIAL SENSES

COSTART COUNT 4 MYORIASIS 1

ACt COUNT 4

COSTART COUNT 12 AMBLYOPIA I

COSTART COUNT 12 CONJUNCTIVITIS 2

COSTART COUNT 12 MYORIASIS 2

COSTART COUNT 12 PAIN EYE

AGE COUNT 12

COSTARTCOUNT 17 ACCOMMODATION WORM

AGE COUNT 17

COSTART CUNT 18 CORNEAL LESION

COSTART COUNT 18 PAIN EYE

AGE COUNT 18 2

COSTART COUNT 20 VISION ABNORM 1

AGE COUNT 20 1

COSTART COUNT 21 CORNEAL LESION 1

AGE COUNT 21

COSTARTCOUNT 23 CONJUNCTIVITIS I

AGE COUNT 23 I

COSTART COUNT 25 PHOTOPHOBIA 2

AGE COUNT 25 2

COSTART COUNT 26 AMBLYOPIA 1 313 __AGE COUNT 26 1 PAGE 110 06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRIO_ADIEACTION CANNOT BE ESTABLISHED WITH CERTAINTY IM1A4 CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

SPECIAL SENSES

COSTART COUNT 27 CONJUNCTIVITIS

AGE COUNT 27

COSTART COUNT 28 DIPLOPIA

AGE COUNT 28

COSTARTCOUNT 30 AMMOPIA

AGE COUNT 30

COSTART COUNT 31 TASTE PERVERS

AGE COUNT 31

COSTART COUNT 32 CORNEAL LESION

COSTART COUNT 32 PAIN EYE 1

COSTART COUNT 32 VISION ABNORM 1

AGE COUNT 32

COSTART COUNT 35 VISION ABNORM 1

AGE COUNT 35

COSTART COUNT 37 VISION ABNORM

AGE COUNT 37

COSTART COUNT 38 CORNEAL LESION

'AGE COUNT 38 1

COSTART COUNT 39 VESTIBUL DIS

AGE COUNT 39 314

COSTART COUNT 47 CORNEAL LESION 06/21/83 CAUSE7EFFECT RELATIONSHIP BETWEEN EACH DRUG- NDiREkCTION PAGE 111 CANNOT BE ESTABLISHED WITH CERTAINTY IN ISM0195

PPA CONTAININO DRUGS

AOE COSTAR! TOTAL

OCCURRENCES

SPECIAL SENSES

AGE COUNT 47

COSTARTCOUNT 49 TINNITU5 1

AGE COUNT 49

COSTART COUNT 54 TINNITUS

AGE COUNT 54

COSTART COUNT 55 CORNEAL LESION 1

AGE COUNT 55 1

COSTAR! COUNT 60 DEAF 1

COSTART COUNT 60 TINNITUS 1

AGE COUNT 60 2 /

__:0 COSTART COUNT 71 AMBLYOPIA uPl; 1-, J AGE COUNT 71 1 CI,. `\'' C' 1/4!

rJ I ' i COSTART COUNT 72 CORNEAL LESION 1 0' 1 cl,1'4 AGE COUNT 12 1 I

BODYCLAS COUNT Ilr e $2

UROGENITAL SYSTEM

COSTAR! COUNT ALBUMINURIA I

-COSTART COUNT BREAST ENLARGE

COSTART COUNT DYSURIA

COSTART COUNT GLYCOSURIA

COSTART COUNT GYNECOMASTIA

3 13 I U '

06/21/83 CAUSE-EFFECT RELATIONSHIP BETWEEN EACH DRUG AND-REACTION PAGE 112 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

PPA CONTAINING DRUGS

AGE COSTART TOTAL _ OCCURRENCES

UROGENITAL SYSTEM

COSTART COUNT HEMATURIA 1

COSTARTCOUNT IMPOTENCE 1

COSTARTCOUNT INFECT URIN TRACT

COSTARTCOUNT METRORRHAGIA

COSTARTCOUNT PROSTAT DIS

COSTARTCOUNT URIN IMPAI1D

COSTART COUNT URIN RETENT

AGE COUNT 25

COSTART COUNT 2 URIN ABNORM 1

AGE COUNT 2 1

COSTART COUNT 3 HEMATURIA 1

AGE COUNT 3 I

COSTART COUNT 4 POLTURIA I

AGE COUNT 4 I

COSTART COUNT 23 AlBUMINOR1A I

COSTART COUNT 23 URIN RETENT

AGE COUNT 23 2

COSTART COUNT 26 AMENORRHEA

AGE COUNT 26 1

COSTARTCOUNT 36 ABORTION

AGE COUNT 36

COSTART COUNT 39 INCONTIN URIN 06/21/83 CAUSE- EFFECT RELATIONSHIP BETWEEN. EACH DRUG_AND REACTION PAGE 113 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALL CASES

r ' PPA CONTAINING DRUGS

AGE COSTART TOTAL- OCCURRENCES

UROGENITAL SYSTEM

COSTART COUNT 39 URIN REIM

AGE COUNT 39 3

COSTART COUNT 41 URIN RELENT I

AGE COUNT 41

COSTART roup 42 KIDNEY FUNC ABNORM

AGE COUNT 42

COSTART COUNT 43 KIDNEY FAIL

AGE COUNT 43

COSTART COUNT 52 URIN TRACT DIS 1

AGE COUNT 52 1

COSTART COUNT 53 KIDNEY FAIL ACUTE 1

AGE COUNT 53 1

COSTART COUNT 55 BREAST ENLARGE 1.

COSTART COUNT 55 URIN REIM

AGE COUNT 55 2

COSTART COUNT 56 BREAST ENLARGE

COSTART COUNT 56 PAIN BREAST 1

-AGE COUNT 56

COSTART COUNT 51 URIN RETENT

AGE COUNT 51

COSTART COUNT 58 KIDNEY FAIL 1. 317 06/21/83 CAUSEEFFECT RELATIONSHIP BETWEEN-EACH 611U&Alt-REACTION PAGE 114 CANNOT BE ESTABLISHED WITH CERTAINTY IN ,ALL ,CASES

EPA CONTAINING DRUGS

AGE COSTART TOTAL OCCURRENCES

UROGENITAL SYSTEM

AGE COUNT 58 1

COSTART COUNT 62 URIN REIM

AGE COUNT 62 1

COSTART COUNT 66 URIN RETENI

AGE COUNT 66 1

COSTART COUNT 10 URIN RETEHT 1

AGE COUNT 70

COSTART COUNT 71 URIN REM

AGE COUNT 77

COSTARTCOUNT 81 URIN RETENT

AGE COUNT 81

COSTART COUNT 82 URIN REIM

AGE COUNT 82

COSTART COUNT 89 INCONTIN URIN 2

AGE COUNT 89 2 v5j

BMWS COUNT 54

'16°44r

~ COSTART COUNT ANAPHYL

COSTARTCOUNT CONFUS 1 nr I

COSTART COUNT ECTROMELIA 1

COSTART COUNT HO DRUG EFFECT 1 06/21/83 CAUSEIFfEq 1 kllin4PIETWEEN_EAC4(1-41iticRTION PAGE 115 IN ALC CAI 16 kIL'ulD WITHCERTAINTY

PPA CONTAINING DRUGS I)

.....i"-Qa ...,-,-, .....: ,/.' TOTAL- _\r/ AOE COS1ART

-0-CUR.go°1!!-P ,...... , __. ._____ "....--.i. ,o. ,,,,0 ,,,,,......

4 AGE COUNT

COSTART COUNT 4 INSOMNIA

AGE COUNT 4

COSTARTCOUNT 6 PURPURA THROMBOPEN

AGE COUNT 6

COSTART COUNT 1 PERSON BIS

COSTART COUNT 7 PURPURA THROMBOPEN

AGE COUNT 7

COSTART COUNT 10 PURPURA THROMBOPEN 1.1

1 00 COSTART COUNT 10 SOMNOLENCE

AGE COUNT 10

COSTARTCOUNT 13 EUPHORIA

- AGE COUNT 13

COSTART COUNT 20 PSYCHOSIS

AGE COUNT 20

COSTART COUNT 21 CORPUS

COSTART COUNT 21 NERVOUSNESS

;AGE COUNT 21

COSTART COUNT 27 ANXIETY

AGE COUNT 27

COSTART COUNT 28 COONS

AGE COUNT 28 319 rr

)

PAGE 116 CAUSE-EFFECT RELATIONSHIP BETWEEN-EACHDRUG-AND-REACTION 06/21/83 CANNOT BE ESTABLISHED WITH CERTAINTY IN ALLCASES

PPA CONTAINING DPUGS

AGE COSTART TOTAL OCCURRENCES

COSTART COUNT 29DEPRESSION

COSTAR! COUNT 29 INSOMNIA 1

2 AGE COUNT 29

COSTART COUNT 31 OVERDOSE INTENT 1

AGE COUNT 31 1

COSTART COUNT 38 ANXIETY 1

COSTAR! COUNT 38 INSOMNIA 1

COSTART COUNT 38 PSYCHOSIS

3 AGE COUNT 38

COSTARI COUNT 42 MELENA

AGE COUNT 42

COSTAR! COUNT 48 AMNESIA

COSTART COUNT 48 INSOMNIA

AGE COUNT 48

COSTAR! COUNT 69 PAIN INJECT SITE

AGE COUNT 69 1 t.,

26 :;0" BODYCLAS COUNT

1040 "GENERICCOUNT 920 317

VIRGINIA MASON HOSPITAL August 4, 1983

The honorable Mary Rose Oakar Hoote-of Representatives 2436 Raburn Building Washington D.C. 20515

Dear Congresswoman Oakar:

I am a member of the Washington State Board Of Pharmacy. Our board for the past 18 months_has been evaluatingthe non - prescription status of the OTC diet medications. _i_was made aware ofyour efforts in this area through media coverage_of the recent Houte_tUbedniaitteehearings. ___I contacted__ Nancy LeaMond and had the opportunity to recentlymeet with Millle_Yinicor. Both_of these_individuals_requeSted that I forwardto your_attention back- ground_material dealing with our review of the OTC dietpreparations. You Will_find enclosed board-titiUtes, newspaper articlesi_and_a_copy of the stat- ute_giving the Board of Pharmacy authority tomove drugs from non-ores-CHOU-on status to prescription status,

My interest in_thit area was initiated byan_article in_the_Seattle PaSt Intelligencer (Or:Closed). As a result of_that_article I--had the-86ardof Pharmacy staff invite to testify at an open_hearingDr- Michael Copass, director-of the emergency trauma in Seattle. center_at_HarbOrvieW Medical-Center here From that hearing_and_subsequent hearings I developedthe opinion that not only were the look-alike drugs an istue that needed to be dealt with bUt also an evaluation of the non-prescriptionstatus of the over-the-counter diet aids.

As can be seen_from_the enclosed BOArd ofPharmacy minutes, a number_of_ individuals- representing differing points ofview had the opportunity_to_ present_these_points of view to the BOArd.Because of the volume of_infor- mation and_the differing points of view, I suggestedthe formation_of an ad -hoc advisory committee to the board. The make-up of the_committee_in- cludes_physicians; pharmacologiSts, pharmacistsas well as a physician revesenting the proprietary drug industry's interest.

Nancy LeaMond has been kind enough to putme in contact_with_Kirk Johnson; the_assistant director of the National Clearing_Houseon_Diet-Pill HarardS at the Center for Stience in the Public InterestMr.- Johnson -has- forwarded me some of the Material that they have developedrelating to OTC diet MediCa= tions.

The Board would appretiate any assistance that your staff may be able to provide

925 Seneca Street P.0, Box 1930_ _ Seattle, Washington 911111 (206)624.1144

27-436 0 - 84 - 21 321 318

us in dealing with this issue. Likewise, if there is any more_that_we_ may_be_able_to do in supporting your efforts -indetermining the_need_for national - legislation related to these over - the - counterdiet preparations; please do not hesitate to contact me.

Respectfully yours _ )4C4A4

A. Zoloth, Pharm. D. Director of Pharmacy _ _ Member, Board of Pharmacy, State of Washington

AZ:11 cc: Board members 319

Legend DrugsPrescription Drugs 69.41.130

RCW 69.41.070Penalties. Whoever violates any Snm1411ty-1977 01.1. a 352: 'If any provision of this act ,ta provision of this chapter shall, upon conviction, be fined application Co any _canon or _cirsumslance_is_held, iavalidrchtlemain and imprucined as herein provided: stet of the act, of the -applicaiton-or the provision to other persons or circumstances is not effected.' 11977 ea.s. a ass 1 101 This applies to (I) For a violation of RCW 69.41.020; the offenoia RCW 69.41.100-69.41.110. shall be guilty of a felony. (2) For a violation of RCW 69.41.030 involving the sate. delivery_or possession with intent to Sell or MOM', RCW 694L110Definitions. As used in RCW 69- the offender shall be guilty of a felony. .41.100 through 69.41.180, the following words shall (3) For a violation of RCW 69.41.030 involving pos. have the following meanings: session, the offender shall be guilty or a misdemeanor. (I) 'Brand name' means the proprietary or trade (4) For a violation of RCW 69.41.040, the offender name selected by_thc_manufacturer_and _placed upon Al shall be guilty of a felony. drug, its container, label, or wrapping at the time of (5) For a violation of RCW 69,41.050, the offender packaging; shall be guilty Of_ a misdemeanor. (2) 'Generic name' -means the official title or a drug (6) Any offense which is a viohtion of chapter 69.5_0 or drug ingredients published in the latest_edition of a RCW shall not be charged under this chapter. [1973 1st nationally recognized pharmacopoeia or formulary; ex.s. c 186 § 7.J (3) 'Substitute' means so dispense, with the practitioner's a utharization,_'therapeutically_ equivalent' drug product of the identical base or salt as the specific __RCW _6941.075Rules---Availabillty of -lists of 'nig product prescribed: Provided, That with the practi- drugs. The state ooard of pharma_cy_may make such ttoner's prior consent, therapeutically equivalent drugs rulesfor the enforcement and administration of this other than the identical base Dtsaltrnay_be_dispensed;__ chapter as are deemed necessary or advisable. The board (4) 'Therapeutically equivalent' means essentially the shall identify._by_ru term king pursuant_to _chapter 34.04 same efficacy and toxicity when administered to an in RCW, those drugs which may be dispensed only on pre- dividual in_thc same dosage_ regimen; and scription or are restricted to use by practitioners, only. (5)'Practitioner' means a physician; osteopathic In_so _doing the board Shill consider the toxicity or other physician and surgeon, denti. ;, veterinarian, or any other potentiality for harmful effect rink drug,thernethed of person authorized to- prescribe drugs tinder the laws of its use, and any collateral safeguards necessary to its this state. (1979 c 110 § 1; 1977 en3. c 352 § 2.1 use. Tie board shall classify a drug as a legend drug where_these_considerations indicate the drug is not safe for use except under the supervision of a pramitio_ner. RCW 69.41.120Prescriptions to contain Instruction In identifying legend drugs the board may incorporate as to whether or not a therapeutically equivalent generic in its rules lists-or drugs- contained in commercial phar drug may be substituted-- Form-- Contents maecutical publications_by_ making specific_reference to Procedure. _Every d_r_ug prescriptgui ShalLcontain an to- each such list and the date and edition of the commer- struction on whether or not a therapeutically equivalent cial publication containing it. Any such lists so incorpo- generic drug may be substituted in its place, unless sub- rated shall be_ available for public -inspection at -the stitution is permitted under a prior-consent headquarters of the state board of pharmacy,ind Shall authorization. be available on request from the board upon payment of If a written prescription is involved, the form shall a-reasonable fee to be set by the board. (1979 1st ex.s. e have two signature lines at opposite ends on the bottom 139 § 3.1 of_the formUnder thelme at the right side be clearly printed the words DISPENSE AS WRIT- TEN'. Under the line at the left side shall be clearly printed the words 'SUBSTITUTION PERMITTED'. SUBSTITUTION OF PRESCRIPTION The practitioner shall_c_emmunicatc_the inittuctionsio DRUGS the pharmacist by signing the appropriate line. No prescription shall be valid without the signature of the practitioner on_one of attic tines. RCW 69.41.100Legislative recognition and declare- If an oral prescription is involved. the practitioner or lion.. The legislature recognizes the responsibility of the the practitioner's agent shall instruct the pharmacist as state to insure that the _citizens or the state are offered to whether or not a therapeutically equivalent generic tip- benefit of quality pharmaceutical _products _at tom, drug may_ be substituted_in its_ place.The pharmacist petitive prices. Advances in the drug industry resulting shall note the instructions on the file copy of the from research and -the- elimination of counterfeiting of prescription. prescription_drugs_should benefit thc users or the drugs. The pharmacist shall note the manufacturer of _the Pharmacy must continue to operate with_a_ccotuttability drug dispensed on the file copy of a written or oral pre. and effectiveness. The legislature hereby declares it to be seription. 11979 c 110 § 2; 1977 ex.s. c 352 § 3.1 the policy or the-state that its citizens receive safe and therapeuticaty_effective drug proclUMs_at the most reasonable cost consistent with high drug quality standards. RCW 69,41.130Savings in price to be passed on to (1977 ex.s. c 352 § purchaser. The pharmaerst shS11 substitute an equivalent

(1910 La.) la,69.41 RCWp 31 54004, fi-lrft **rt./ fr>1?-1/11 4-1/4 of 6.4,1 411 . tiPil t , tf .,i-r1-il ' II _111 i .1:It:.; 1Ilti 4 :-.illla it la (t. ,a,.. toeat. 1 w .t:-.... . t r ,i1111 II lig,1i!iimPAlimlli!4iigilatilitgltentui4 .-sli t?1,4 a' I. i . .0..101 t!tiiti. ig I I 'Ada it iigainfitAiirAnit,i!!.;3!1.11,..g.11ifLpiLmJ,vereit..ti . ii ottlitoi.111 Kea hazards indiet gills told byscientists KfighlNiws Barka imingiinimo However, even they_concedi_ that.rkat kit* dh 6=144 dints taking PPA- normally lose-ordy abouthlad prom ad a low pieate de J.1961i1NOTOR-kllmprincipal egredi. I ee In die pills, on which AMAtiCalitiOrld cikt itttl mtstelkal Irsv feViy.g more that $10 million a ysr oily a;softiies - hi-red *sok for fruldetinetripttib Thidskb _Eva the mammy of amessiitho mid the drug inellectivebut CUalso pravike strokes; iz musk tun to !sifter stroka cerebral hemonteges and-high- bloolipres, "I Mk vm'm laths mattestak dlet0.111 to ia welOt hid Oa sa, a prel .iiiicienties lida Lai ter ulkomiliti-wasau4" she here," saidDr, Matthew.rid1evof y,4 ad, "Alta thva tsji; I WO .1 ray ftleM6110401=EM0.1.0100111,1111000111101biohfind-Hart Wit whoial 14111A VI _apOth- saxes. kir! Owed my kee leo loth 114 OD I I 111,r I Ica* sat are illtddft teen.a : em see.11! i Non iitta" tptbleinitntiiiiik"iald Dr. Thaddesblood tau that PPA hu mit Prouit a calcalliatialoilitat tittJ E'Jefktf atheir hgettk. IDA}-11m- art le, fet liojkuis beaky -Sc of Mettle" ts agate'.114"., METINL010 er Ii_whitictilii.l.knerian (th-OPA-auss11100." itiotintriti if ow itts#01_n pure. _tme giant said the the-The Canter F'Ute Itt Pilk del takenIn totainatlajth a Pe frai It should It treated Gjj aMr from INA Willl'arieldrtoto the motto &up, can result In "a impos.fraud and got" bra* -1 , 11 IDA D'Amrdier sIbIstskolop)al ituadon," The findinp of the ;1.044were AMA 111-11*-0-Witi, trOksvo-kid .2fte scientism, Oiled fournle whovIguttplitutidowever, -by a mem oflost stemming from her IR stroke. a tathi they ad altered seam radars, Mt tzli1 pveirol Iiii4 to* elett Melia ad medial _resaMhetsMthei tioje-kid --Conreciut litcloti.strokes..ifteriskint pb_raide sent to .the heuing-by lova Medial mid ter 6x* It kg_ ti witlt, .11 1, ko; tki,ouN, on the Ckynt,lorianulatimitt_PPA,-They webral-hemortio II 14 Mimi- kg n, _to, ler k the do 6 not Misted their reach it* tatthe dig yton AM* *lir t L vitt Ikt hi RI kilt of OA 1101 .641itts.arto lom toOlostliOlts to her bg dig , ,i 11 0101 wolla; e, risk una. i rent4 (icily* d 41 t4 322

THE FOUR HUNDRED AND THIRTY-SIXTH MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

December 3 and 4, 1981

The tour hundrCti_and. thirty-81*th meeting of the- Washington State_lleard.Of Pharmacy was called to order_at. by- Chairman Arthur Zoloth in the conference room of the King County Precinct 4i 14905 Sixth Avenue SW; Burien; Waghington_, on Thursday, December 3i 1981. Present were Chairman Zolothi Vice-Chairman Lars Hennum; Board Members Harold F. Osborne, David H. Palmer, .imd Fdvrn H. Jones; Executive Secretary Donald H. Williams; Chief Investiga- tor tbirles James; Barbara Phillips, AAG; and Mary-Helen Hansen, clerk.

Mr. John Welsh, Counsel, speaking on behalf of Chairman James Mitchell of the House Human Service. Committee, presented and discussed a proposed amendment to the Controlled Substances Act-which would prohibit the sale of imitation controlled_substanc-s f"look-alikes"). _The amendment is based on a_Model_Act developed by the Drug Enforcement Administration for_consideration by- individ- ual states._ Presently sixteen states now have some legislation in thin_area. The PrOposed_legislation would outlaw the manufacture;_dittribution; and poll- session of "look-altkes"; or imitative controlled subStances; tind_plug_a loop-

- hole in the present law. The present law makes it a crime to sell a fake controlled substance fraudulently. This Bill addreases the question of nttempting to sell or selling something that looks like a controlled substance , without representing it to be a controlled substance. The intent of the seller is co pang the drug off to the buyer as a controlled substance for resale, so Oat the buyer ends up making an inordinate profit, representing the drugs not directly as controlled substances.These drugs have been made to look like controlled substances and made in- concentrated quantities of caffeine, ephedrine, phenylpropanolamine, and other_substances_that may cause injury or even death_ to nsers. The market is largely youth fro,* adolescence through college. The

advertising is-open and nonsecreriVe. _Purchases can_be made by_maiI_or at _ truck stops_, "head sbops"_; and other places. These drugs are illegal in Wash- ington if they contain ephedrine.

Chairman Zoloth asked Mrs. Phillips if the Board had the authority under RCW .8.64 to promulgate regulations on "look-alikes". She replied that criminal penalties could not be created by regulation, and that while the Board may or ,ay not have the authority, statute would provide the stronger penalties needed.

The Bill defines "imitation controlled substances" and addresses intent to deceive by the seller.Also it creates crimes, prohibits advertising, lists exemptions from liability of the Bill, contains provisions for seizure and forfeiture, and adds a new clapter to Section 69 RCN. No problem is anticipated in passing the

Board_members: suggested that the amount of_tablets in possession be considered as intent, to sell: expressed concern about legitimate OTC products now in the pharmacy; and questioned the possible abuse of phenylpropanolamine 1PPA) and the need for Board action in this area. Mr. Welsh suggested that the Board hold a 323

public hearing on PPA abuse with input from concerned parents and school personnel.

Mr. Henn= moved- that- the-Board -draft a resolution in support of_the_Proposed legislation- dealing with imitation controlled_substences_i_and_that_the 1'1417 vidual Board_menibers - as they personally feel - may submit-Individual-statements as well. Potion passed.

Mr. !lennum moved to-scmd-a letter to-the-legisiatort that they consider removing the lafrile-statute as--Chime-have -iftarti-no-applications for manufacture since end-cm-eat Motion passed.

The Board discussed the advisability of requesting the legislature to place ail_ DMSO OP prescription status as rec,mmended by the DMS0 Task_Force and determined that a letter should be sent to the Joint Administrative Rules Review Committee recommending that all OHS° sold at retail must meet the purity standards set forth by the Board.

Braid members discussed abuse of PPA products and requested that the Board office contact manufa:furers, N1DA, Board inspectors; the State Medical Association, a pharmacologist; and poison control centers, as well as concerned organizations of parents, and inform them the Board Is considering making PPA a legend drug and will hold a public hearing in the near future.

Mr. boc Nguyen of Saigon Drug, wholesaler, appeared before the Board to discuss his proposed operation of packaging and exporting legend drugs to Vietnam. The Board had deferred action on his application (October meeting) for a_wholeiaIer Pavkaged legend dr,,gs purchased by his customers are sent by hiit Are,t1v to private Individuals in Vietnam via Air France or the V.S. Postal

Mr. nsborne moved to gram the wholesale license. Motion passed.

rh Board reviewed Oregon's wholesale taw export section as a possible model for a Board regulation for wholesalers.

Mr. Palmer mayed-co-thaft whol-e,ol-er- regulations using. the Oregon law with arn -Wa-shington regulations. Motion passed.

Mr. Pernum moved that both Mekong Pharma Inc. and Sailon Drug wholesalers - start keeping records along the line of what will be i__proposed regulation so that of the rim,: of thc regulation hearing, they can gIVe input as_to_the accuracy of ,v!zords, ant stirtjteepfng records in the correct manner - and that this be stated by letter. Motion passed.

Mr. Jones asked that the Board staff assist the two exporters in setting up record procedures.

Mr. Phillips adyiera that she will file these regulations for a formal hearing FL.hruar!:.

Mt. Nrhia Doan explained the oporationsof Mekong Pharma Inc. Both wholesalers were thaked for appearing End explaining the procedures and for their assistance la, the hoard.

32? 324

THE FOUR HUNDRED AND THIRT"-EIGHTH MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

February 18 and 19, 1982

The four hundred and thirty-eighth meeting of the Washington State Board of Pharnocy was called to order at 9:18 a.m. on Thursday, February 18,1982, by Chairman Dr. Arthur Zoloth In the conference room of King County Precinct 4, 14905 Sixth Avenue SW, Burien WA. Board members present were Chairman Zoloth, Vice - Chairman Lars Hennum, Harold F. Osborne, and David H. Palmer. Board Member Edyrn H. Jones was excused for illness. Board staff members were Donald H. Williams, Executive Secretary, Chief Compliance Investigator Chailes James, AA0 Barbara Phillips, and Mary-Helen Hansen, clerk.

Chairman Zoloth_opened a_discussion of_the abuse potential of_cough syrups containing codeine and the_dangers of Phenylpropanolamine (PPM; Dr; Zoloth introduced Dr._,awrence Halpern, Department_of Pharmacology; University_of Washington Health Sciences. OrHalpern had been invited_by the_Board_to_ discus. the appropriate use of codeine in Schedule V cough syrups and phenylpropanolamine as a drug in diet aids and "look alike" tablets.

Or. Halpern felt the Board should consider:

I) After two or three weeks, people are buying the cough syrup for other than cough suppression.

2) Does the volume amount in a 4 oz. bottle of cough syrup fit the time covered for use?

3) Codeine vs dextromothorphan: dextromothorphan is not as effective as _a cough suppressant - not as good a centrally acting drug as it is an anti-tussive.

4) The tic-in with alcohol in the cough syrup is the attraction for abusers.

5) Is the practice of selling the cough syrups by the pharmacies contributing to drug abuse?Good pharmacy practice?Good medical practice?

6) Home dosage; patients increase dosage. A drug should be taken according to instructions. If it doeK not work; the patient should check .back with the physician for other medications.

7) PrescriPtion only? Check with chest physician for prescription or non-prescription informatiom It may not be needed for long term use.Perhaps the MD is restricting prescriptions.

8) Ineffective home remedies. The cost benefit - the charge for prescriptions by the physician and the pharmacy.

328 325

In summary, Dr. Halpern suggested the Board seek guidance from a pedia- trician and a chest physician concerning amounts of codeine cough syrups to be prescribed.

According to Dr. Halpern, phenylpropanolaMine was a third generation diet_ pill, a decongestant with_the same potential for adverSe action as amphetamines: Paranoid toxicity due to increased dosage, _plus deep;_long7lasting depression. It was not approved by the Food and Drug_AdMinistration, but by a panel appointed by the FDA who approved it for weight control. With "look alikes" the danger to users was overdosing on real "speed". PPA was a useless kind of medication that was not effective in weight loss over a long period of time. The patient was treating depression rather than the weight problem.

Or. Michael Copass MD, Harborview Hospital, Seattle WA, stated that very few people need a chronic cough syrup, possibly only those with smokerfs cough._ _ _ Self medication ha; become a national habit. The abuse potentialfor - Schedule V cough syrups is moderately high. Pharmacies selling most of the Schedule V cough syrups may be located in an area where much drug abuse occurs_._ 48 hours_ between sales to an individual may be -too short. He suggested the Board should find out what the pharmacists are saying to the patients about its use.The pharmacist may need more control over_the frequency of allocation. He felt that codeine was not neededin_lhematter of_phenyipropanolamine Dr. Copass related some statistics: Although Ritalin was still the largest drug of abuse in Seattle In 1981; Benzedrine was second. In July 1981, there were two emergency PPA cases at Harborview Hospital, in December 1981, there were 50. In the middle age group, it was diet aid PPA's, among teenagers, it was "look alike" PPA'S:___ He felt that this was just a beginning. Dr. Copass discussed the effects_of PPA - hypertensive hemorrhage due to malignant hypertension, a tremendous ':buzz", Severe agitation, and - after treatment - -a deep depression.He stated that "look alikes" needed to be looked at by both the pharmacy and the medical professions, because it needed to-be stopped. _"By allowing the medicines; we are generating a patient population", he said.Two to three mg's per_day were all right as a decongestant., 65 to 85mg'S could be tolerated as a diet aid; but 85 to 200 or 300M§'S per day resulted in very high blood pressure._ The attraction is in the "head Set" Or mental effect that this so-called "speed" produces. Dr. Copass agreed that.both cough syrups and PPA products were in question as to clinical effectiveness and may add to the drug abuse problem In the community.

Mr. Norman Johnson of Therapeutic Health Services, a drug abuse_program_inSeattle, discussed the use of cough syrups among the clients he is treating Ari his clinic. Most of them condemn the use, but most use it to tide them over and prevent _ withdrawal symptoms. He stated that he was not aware that the use was so wide spread. He was very upset at the ease_with whith it was obtained.The drug users were -now getting alcohol in addition to the_codeine. He is very concerned that the 60 day stabilizing period for his_cilents is being offset by the cough syrups that_they can get_very easily. He felt_that pharmacists should be given some controls over the diSpensing of cough syrups. He questioned the amount and frequency of avallability_of_the_medication,_and the prolonged sales to users. He had not seen any PPA use to date. He introduced Debbie Fisher, a client in his program for pregnant addicts.Mrs. Fisher discussed her knowledge of the easy availability of codeine cough syrups and amountof money and effort spent by users to obtain a supply. Four and five bottles per day was an average use; $500 to $700 per month was spent on bottles of cough syrup.She described the

29 326

THE FOUR HUNDRED-AND THIRTY -NINTH MEETING_OF_THE-WASHINGTOH STATE BOARD OF PHARMACY

March 18 and 19;1982

The four hundred and thirty-ninth meeting of the Washington State Board of Pharmacy was called to order at 9:05 a.m. on Thursday, March 18, 1982, by Chairman Dr. Arthur Zoloth in the conference room of King County Precinct 4, 14905 6th Avenue SW, Burien, Washington. Present were Chairman Zoloth; Vice-Chairman Lars Hennum; Board Members Harold F. Osborne and David H. Palmer; Executive Secretary Donald H. Williams; Assisi. ant Attorney General BarbarA Phillips, and MarrHelen Hansen, clerk.Also present were Chief Investivtors David Campbell and Charles James, and Board Investigators_ Willard Scott, Frank Bracelin, Hobart Ashmore, Bob Miller; and Dick Morrison.

Chairman Zoloth announced that the formal regulation hearing scheduled for 9,00 a.m. to repeal WAC 360-16-110i the old Hospital Pharmacy regulations inadvertently left In effect when chapter 360-17 WAC was adopted, would not be heard because of a problem with notices. The hearing will be continued to the April meeting.

The Board then met in a Closed Meeting with the Investigators.

At 10:25 a.m. the Open Meeting was resumed. Chairman Zoloth announced that the Board of Pharmacy had the authority to determine which drugs_were legend drugs, and the Board was considering makinr_Phenyipropanolamlne_a legend drug. The Board had asked representatives from industry and medicine to_present_information on Phenylpropanolamine (PPA) for a proposed regulation hearing.

Dr. Edward Steinbergi Ph.D., Vice-Chairman Thompson Medical Company Hew York NY

Dr. Steinberg stated that the Food Drug Administration miscellaneous internal review panel of physicians (report published February 1982). recommended Phenylpropanolamine as safe -and effective for appetite_sup- pression for weight control for a period of use of 12 weeks when used as directed.- PPA-has been used for 40_years as anappetite suppressant. An estimated 10 MiiIrOn people_currently take a weight loss product. Itis a proven aid to weight loss with no significant changes in blood pressure; pulse rae, or side effects. The FDA panel conclusion was based on clinical and laboratory studies submitted by Thompson Medical Company and others. The studies were based on hundreds of patients with thousands of patient days under medical supervision. There are no new statistics to indicate itis unsafe. The legal dosage In -the United States Is 25mg three times per day, or 75mg total once a day in a time release capsule. Dr. Steinberg believed PPA to be without tolerance or abuse potential. In Australia, according to an article In The Lancet (1980), an 85mg Immediate release form caused some elevation in blood 327

pressure.

In tests with animals - -rats and monkeys - PPA- reduced -food intake with a lack of hyperactivity and stimulatory effect. Human studios show that the weight loss from use of PPA was at least equal to the weight_loss by any prescription drug, with none of the attendant sideeffects, and twice as effective as a Placebo under clinical conditions. This product is important to millions of consumers who are motivated_to take off weight and need such a modality. He felt that young people who may be trying PPA for purposes of achieving a "high' will be disappointed. A check with all related federal agencies, plus checking with researchers who had conducted studies with 13,000 teenagers (federally financed study of drug use with numbers of drugs) showed no PPA abuse. PPA was not listed separately by Poison Control Centers of DAWN (Drug Abuse Warning Network). The data listing 10, 000 poison control cases with 1000 Emergency Room incidents involving PPA weight control products occurring each year is not true (Vol 25, Ak,gust 1581, Bulletin National Clearinghouse for Poison Control Centers). The figure is an estimate, aCCOrding to the_serilor author of the report. 739 was the actual number. None of the 10;000 cases has been checked out _He felt that the statistics were picking up the use of street drug "look alikes".

Caffeine_ is included in diet aids to offset lethargy caused when an individual goes on a reduced caloric intake. His company produces products both with and without caffeine. Dosage of PPA permitted by the FDA for diet aids is 75mg per day; for the cough and cold industry, it is 150mq per day. Studies indicate there is noproblem with higher doses -150mg -in a 24 hour period.

Dr. Steinberg stated that the illegal drug "look_alike" problem_was a matter requiring appropriate federal and state scrutiny and general improvement of safety precautions in the home. Thompson Medical's packaging and labeling precautions_ were effective and responsible and should not be penalized_ because Others are making "look alikes". He quoted the_consumer member "watchdog" of the FDA panel, Michael Shulman of USC, as saying he was impressed with the evidence and in his judgment PPA was safe, effective, and in the best interests of the public. 12 weeks were established as a time frame by the FDA because Thompson Aedical_had submitted studies up to 12 weeks. His company is updating data on longer term use. There are nostates that currently_require prescription for these products. Thompson is an OTC company with no prescription products and would penalized by a vast reduction in sales.

Dr. Steinberg introdoced_Ms. Sunny Wilson_i Cosmopollsi Washingtonwho talked. about her use_of PPA._She_lost 78 pounds in 12 weeks with the use Of a Thompson product. She had tried other diets without success. She has maintained her achieved weight for over six months. She takes one capsule per week or as needed.

331 328

Dr. Harold 1Silverman, Ph.D.; RPh. Professor of Pharmacy Executive Director, Pfifer Research Laboratory Massachusetts College of Pharmacy Member of Faculty, Boston University School of Medicine Consultant to Thompson Medical Company

Dr. Silverman stated thaZ problems, if there were any, were_not_due to the legitimate use of Phenylpropanolamine. Used appropriately in correct dose, the drug_wis safe and effective. Mis original research found the drug to be efficacious and net to produce any adverse effects when used appropriately. He cited a report from the national Clearinghouse for Polson_Control Centers; reporting incidents from all drugs -- 65-66 ;000_ incidents - that there were no reported deaths from PPA; though there were many from other drugs. He felt PPA was incapable of being abused and Incapable of being used in a way which would cause either euphoria or stimulation. It was an effective nasal decongestant and effective anorexient. He felt that because it falls within the category of Central Nervous System stimulants, that itis assumed that PPA will have a stimulant effect.

Dr. Silverman felt that "look allkes" were the pioblem._ Uith regard to caffeine and PPA, DEA felt that more deaths from caffeine overdoses may have gone unreported.There were no deaths_from PPA. Thompson studies had not shown a synergistic effect for PPA and caffeine together. PPA did give a feeling of disphorJa, but no euPhorla. In independent Studies atAllins Hopkins University involving primates, higher doses had sho., no drug abuse or bizarre behavior.There were no published human studies. Overdosing with PPA, caffeine, or a host of other substances will increase blood pressure. There were no problems in studies as submitted to the FDA where 75mg to 150mg per day were used.

Dr. Silverman discussed the study done by Horowitz in Australia on a product not available in the United States. It_was_not_the same as the U.S. PPA. There were four different isomers of PPA._ DL_racemie was the form used in this country. In Australia, it was D_PPA;_the_dextro form,_35mg, immediate release. He had not received enough tablets to test for increase in blood_pressure. This product was no longer on the marketin Australia. The study was only to be used as a guide. He was not aware of hypertensive incidents in this country the same as Horowitz reported in Australia. There were no deliberate studies being developed with humans with regard to high blood pressure or toxicity because of the risk. He was not aware of adverse effects in either the blood forming organs or the cardio-vascular systems.A lot of PPA has-been given, but the studies only run for about three months at a time. Statistics have only been developed over the last 13-15- months. Thompson Medical is mapping out what it will do next with data for long term use.

John Grunzell_MD_ Professor of Medicine Department of Medicine Division of Metabolism and Endocrinology University of Washington Seattle, Washington 329

Dr. Grunzell explained that he was-interested in the 1,001)9°4 Of obesity and would discuss the problem from the viewpoint of ic;, physician._ Obesity was_both a health problem and a soaleicti. problem. The health related problems were problems with blvi. Li0F/ diabetes: high blood fat levelqtriglycerates or chloreStere '411d elevated blood pressure. Al] of_the_risks for obesityfor Peatib't disease and strokes_seem to Iv: mediated through one of these[ IN diseases. He stated thatit has been demonstrated that WeigM fleet!"s would ameliorate all of these abnormalities, so there was a to find a system so that people could take off weight and keep -i. 'ff. There were many ways to lose weight, including diets, behavi°__21Ni, fication, and drugs. Weight loss was not the problem, Oole-T: of weight loss after the desired weight was lost was prorf'41_, Today, there was no way to take off weight and keep it off, -f followed the patients over a_number of years. -Two pel.oent-°- population could_take off weight and keep it off_for ojne ye and Thera was very little data other than short term folloseuP_°°, ance of weight -loss to indicate that drugs are effIcaoos0 O--I-t efficacious. Drugs available Include adrenatin-like;amohetainnbi. like (Fenfluoramine and PPA may be a separate subclasq; thyr761- like, no longer used; and other drugs which block the jbiorild Of certain kinds of foods. Amphetamines and PPA are anoPDXi° a h up secretions, which is the reason- for the use of PPA In coUght4Yrue. Most have a Central Nervous System effect.Many help in wei! ti.1455' There is not much evidence to suggest that PPA does much m°(- help weight loss than the desire to lose weight alone.

Dr. Grunzell quoted from ThonpscnMedical_Company!s own contra cqtions 1,t: as- published in the Physician's Desk Reference for the 75reg

"Do not exceed recommended dose. If nervousness, diazlno5!.., _ sleepiness, rapid pulse, palpitation, or other symptoms 007.i% discontinue medication and consult your physician; jf YOU,ea e or are being treated for high blood pressure, heart; dia'e's. thyroid; or other diseases, while pregnant, or nursing_ tinder the age of 18_,_ do not take this drug except under the advice of a physician." He identified those people who are overweight or who have 0w;,4,,esitk associated with a health problem, other than the massively -°vi individual, as people at risk for stroke, for heart attocks Fated to diabetes, high blood fat levels, and high blood pre oure!_ Or thesc people, he felt the drug was contraindicated, according 14 Thompson Medical Company. 4or, In summary: I) He was not surc there was a successful iddY f surgery for keeping weight off once the person had lost_the i'eqh17 2) If there wa a to take weight off and keep it tiff. frcraZ,ve5 n° data_on long7term weight maintenancei_using_any of_these_01°,, e "Zins compared to simple caloric restrictions. There was no dOue'C t5Ir reasone efficacy. 3) If a study is done, he feels there Is no -cliePt PPA over Fenfluoramine, or some other drugs. Finally,if the!,_PAA jruti arc important and individuals who need these medicatioo5 are LOtjf(eda Dr. Grunzell felt they should be regulated by a physician-41e 41d /°°k for the risk factors and take care of the potential problems' 330

Dr. Stephen Woods, Ph.D. Professor and Chairman, Department of Psychology Department of Medicine University of Washington Seattle, Washington

Dr. Woods commented_on PPA; There were no published longrterm studies on the efficacy of PPA._ There is a high tendency to regain weight. He quoted weight loss studies at Princeton: People who received a Placebo lost 11 pounds over a 10-12 week period, while those who got PPA lost 21 pounds over the same period. (NOTE: We believe Dr. Woods meant to add "per week" to the pound figure quoted.) The combined effect was greater than PPA itself. He felt that It was significantly higher than the placebo effect or the desire to lose weight. He felt the evidence was in favor of the concept that PPA does act by getting into the Central Nervous System, the sited action Is in the-same part of the brain that stimulation occurs. There is a big void in the literature. Many drugs are not being_tested by psychologists with_ regard to the ability to reduce appetite and to take off weight. A series of control experiments need to be done to show that these drugs are acting in_some natural way on the appetite systems. There are no Studies on PPA: Does PPA_cause_an_averslon reSponse - taste aversion? In_common_testlng, the drug is given to animals to see if when they stop eating they undergo the same behaviors that they undergo after a normal meal, but that this Is happening sooner in time with the drug. The test Is called complete behaviorlal satiety. This has not been done with PPA, though it has been done with other drugs In that family, and all cause very large disruptions of normal behavior. Finally, a critical study would be the degree of-weight loss over a period of time and_the ability to keep the weight off, given_the prescribed regimen. He felt the Board needs to weigh -the poteritlal_for beginning to lose weight and maintaining that regimen for a period of time -_ In addition, the number_of people who are seeking to lose_weight withOut_consultIng a physician r against the real efficacy of Phenylpropanolamine and a possible potential for abuse.

Mark J. Ugoretz Assistant General Counsel The Proprietary Association Washington, D. C.

Mr.- Ugoretz identified The Proprietary Association_as a one hundred year old-trade association representing manufacturers_ of non-prescriptiOn_ medicine whose product, are marketed throughout_ Washington. He stated that he had been working on the_issue of street drug "look ailkes" for about two years. Me referred_to the FDA panel report that PPA was safe and effective as a diet aid and did not require supervision for use. PPA seems to be connected with the abuse of drugs In unapproved combinations such as caffeine, ephedrine, doxylamine, and other ingredients. These are misbranded and have no NDA. He distributed documents to the Board that reviewed the laws with regard to "look alikes" and gave background information on the issue. 43 states are looking at this problem 331

which does not Include legitimate OTC drugs sold in retail outlets.

PPA appears to be-used to permit the drugs to masquerade as legit- ovate- products. 17 states have-passed laws; 26 are still consider- Ino_it- (NOTE: _Washington legislation was attached to another House Bil1_than_1315 and paSSed.) In states -that -have passed bills hasedon_the DEA_Model legislation,Or_the AMA bill, the distribution and abuse of_street drug "look allkes" has deelitied: Not one Of the 43 states has restricted PPA to prescription or anyway priVinted consumers from obtaining diet aid products. In his travels through other states, he has discussed PPA and other states do not appear to have the problem. The problem of PPA showing up in reports will be resolved when the "look allkes" are outlawed. He asked the Board to provide his Association the opportunity to examine data, the Specific number of actual Instances with legitimate OTC products containing PPA that were-purchased for Improper use, where purchased, and by whom. (He_was told that the Board's responsibility was to the Public; and that if the Board found sufficient- reason to act, it would,) _He_was not aware of the problem in other states.- He warned that_Washington consumers will suffer the Inconvenience-of loss of outlets_if_PPA_is out-on- prescription status. There Will_be_Orice increases and the need for doctors' visits and_the prescription prices added -if the product can be_found. OTC products will be purchased out-of-state. The products will be misbranded, unless the pharmacist attaches a state legend label.He urged the_Board to await passage of legislation regarding "look alikes". In summary; PPA was a safe and effective drug. In other states which had considered legislation, abuse was found to be in conjunction with other drugs and fraudulently sold as street "look alikes".

Dr. Raymond Ragland -Ph.D. Henley S James Laboratories Division of Smith Kline S French Philadelphia PA

Dr. Ragland stated that his company had been in contact with poison-__ control centers and their data was inconsistent with what the Washington Board of Pharmacy's data suggests.

Dr. Evari.G_Sligal _ _ Scientific Affairs Associate The Proprietary Association Washington; D.C.

Dr. Siegal explained that his background was In molecular bielogY; pharmacology, and toxicology, as well as medical genetics at two universities and the FDA. He reviews literature and reports - Informa- tion from federal agencies and poison control renters, published and unpublished literature, reports from consumer groups, and mortality and morbidity reports from the Center for Disease Controlin Atlanta. He was a PTA president of his son's school and alternate delegate to the county Board of Education in Maryland. Any information regarding drug abuse would come to him. He suggested that althougth PPA resembled 332

an amphetamine -like- compound, it actually oay prevent some of the Stimulation that is known to be caused by amphetamines. PPA is known to be excreted_by humans at a rate of 97% unchanged in the urine in 24 hours.,A reoeptor binding and blocking action may eventually be Proved to occur. The "olamine" at the end of PPA can controlled sub- - to the uneducated mind - be likened to amphetamine %Lances. The kids may be linking "look alikes" to PPA and grabbing diet aids to get a supposed "high". He has no data to show, but_he feels it is human nature to look for other sources when one particular source is not available. He cited the unstable psychOlogleal state_of_ teenagers - they would take anything and continue to -usewithout effect. The supposed effect may be psychological_responSe. He quoted from the 1931 report of Poison Control Centers: No inferences should be drawn from the data concerning the true incidents of poisoningsigns and symptoms, hospitalitation, death, or other aspects of theproblem". The reports are basically anecdotal and may have nothing todo with adverse effects - cause and effect - of PPA.According to DAWN, the peak of the PPA cases were teenagers 14-18 years of age.There was rOthing after the age of 18 in incidents of PPA relatedeffects. There are IQ million dieters who are in the adult agepopulation. In the latest data to December 1981 from Emergency Room visits,--PPA related incidents had dropped two-thirds in the last half of 1981.- suggested that the Board may have part of the answer nationwide_to theinOrease of Emergency Room visits due to PPA.There are very fewonalyses of what drugs were present in reports, they are mostlyanecdotal.

All speakers were thanked for their contributions and time.Hr. Williams requested the source of the 739 PPA incident figure reported byDrs. Steinberg and Silverman.

Cha.rman Zoloth reconvened the afternoon session at 2:CI p.m.

Steve Smith,Assistant Attorney General, presented the ollowing Order:

Jimmie AdonT-i-bbe-t-s---RP-h. I Claliam Bay WA

Possession of legend drugs_without prescriptions o- orders,possession of controlled substances without prescriptions or Orderls.

rinal Order on Stipulated Settlement: License suspended for 5 Years, 4 years stayed, unless further violations of any state orfederal law, tul6 or regulation relating to the practice of pharmacy during a5-year peind, beginning w' the date of this Order. Prior to (reinstatement:

I) Participa: o drug abuse program approved by the!Board and provide evld, e of such participation.

it would be 2) Documentation by two professional therapists that appropriate to reinstate license.

3) Take and as the law exam. 333

THE_FOOR_HUNDRED_AND_FORTYTSECOND MEETING_OF_THE_WASHINGTON STATE BOARD OF PHARMACY

June 24 and 25i 1982

The four hundred and forty-second_meeting of the_Washington State Board of Pharnacy was Called to order, by Chairman Lars Hennum at 5:13 a.m. on Thurs- day, J05,2 24; 1582.in the conference room of King County Precinct 4, 14905_6th Avenue SW, Burien, Washington._ Those present were Chairman Hennum; Vide-Chairman Harold F. Osborne; Board members David H. Palmer, Joseph J.' Thompson; and Dr. Arthur Zoloth; Executive Secretary Donald H. Williams; Assistatt Attorney General Barbara Phillips; and Mary-Helen Hansen, Clerk.

The meeting opened with a presentation "Look Alike Drug Research and Physi- cian Training Project and Diet Aid Misuse and Abuse" by Drs. Donald R. Wesson MD and John P. Morgan MD of the Drug Look Alike Research and Training Project, 405 Clayton Street, San Francisco CA 54117, associated with "light-Ash-

bury Free Clinic in San Francisco. OrWesson, a psychiatri: , ',strata his report with slides which showed look-alikes, drugs of decept. stimulants, diet pills, and cocaine look-alikes.- Since amphetamines have been traditionally the drugs of abuse, fake "speed" Is manufactured to closely resemble legitimate amphetamine tablets In form and marking, as well as containing chemicals known to produce_a similar mood effect:- e.g., caffeine_ehhedrine,_and phenylOropandlatnine. The danger to youthful drug users is In their consuming a large,_multi-unit dose. Dr, Wesson_stated_that_hls_research_has_falled_to turn up information On medical or_psychlatric_coMPlications from escalated doOgei of OTC diet pills by chronic users."Look-alikes" are not viewed as and are unlikely to be used alone in suicide attempts.

Dr. Morgon;_is Medical Professor and Director at the Pharmacology Program, Sophie Davis School of Biomedical Education, City College of New York. His presentation began with a history of the amphetamine popularity of the sixties which resulted in the advent of look alikes when the DEA action to place amphetaminesin Schedule 11 of the Controlled Substances Act successfully curtailed manufacture of amphetamines. The triple combination of caffeine, ephrJrine, and phenylpropanolamine has made up the bulk of stimulant sales, and nearly all deceptive products contain this combination.- According to_Dr. Morgan, no legitimate OTC preparation Is manufactured in_this triple combination. Manufacture and mall order sales of Icok-alike_pills_becamemvident in the late seventies and are now-widespread. Ads are_directed toward bulk pur- Olaies and resale is-encouraged. The_initial reaction by our culture is to____ respond with anger, fear, concern, and to formilate laws. Dr. Morgan felt that evidence that these drugs are dangerous_is unconvincingCaffeihe_IS_used daily by Millions, and ephedrine and PPA are_used_Successfuliy_as_broncho7 dilater and decongestant. Dr. Morgan sui_gested_that states_should_wait to see What_the Fedetal government initiated witn regard to curtaining look alikes. The Federal _government has already shut down several illegal manufactures, 5s COUnterfelt drugs are adulterated and mislabeled. The Post Office has en- joined mail order advertising at this point. Self medication is part of appropriate health care and should not impaired by restricting access to these agents such as OTC caffeine, ephedrine and PPA. Dr. Morgan admitted that PPA

1.3 3 7 2"-436 0 84 22 334

is hyper'cnsive, but stated that hu did -not know what effect massive doses would have on the user. He flJJ heard of several repor%ed deaths from overdoses of look-alikcs, but the medical evidence was not complete. In response to questions from Beard members, concerned that the evidence presented was contrary to presectations from University of Washington physicians and pro- fessnrs, Dr. Morgan confirmed that money for their research comes in -part _ from manufacturers and members of the The Proprietary Association. However; he felt the Board's concern -and interestin prescription only status was valid; and he doubted that the caffcine/PPA diet aids were significantly therapeutic in the long run. He did not wish to see over- regulation of drugs for "people's smn good" while responsibility for one's own health was now becoming the mode in American life.

Requests for exemption from the Imprint law deadline were considered by the Board!

Abbot Laboratories - Paradione *Continue to next meeting.

Upjohn - request for further extension of time. Mr. Rogers of Upjohn was present at the meeting. *The Board voted to grant extension tc Janu / I,1983, for the following products contingent upon receipt of a letter of Intent to comply from Upjohn:' Maolate 400mg, Fcminone 0.05mg,Pamine Bromide 2.5mg, Cortef 5/1-0/20mg, Didrex 50mg, Provera 2.5mg, Delta Albaplcx, Albaplex,.Lincocin100/200/ 500mg(Veterinary), Cortaba(Veterinary), Panmycin Nydrochloride Bolus Veterinary, Hedrol Img(Vet).

Endo Laboratories - Tessalon Perles will be Imprinted per letter of 6-22- 82 requecting extension to October 1, 1982. *Board approved extension to October 1,1982 - then unimprinted products must be recalled from wholesalers in the state.

Dura Pharmaceuticals - Dura-Vent, Dura-Vent/A, and Dura-Vent/DA all will be imprinted by August 30, 1962. Mr. Wheeler and Mr. Evangclisti were present to request extention. *Board granted extension continent upon letter of intent.

Winthrop Laboratories have notified the Board by letter that Lumino: Ovoids will no longer be manufactured.

Dr. Zoloth requested that regulations be developed that would require manufacturers to update inrormation and presPrit it in Standardizedformat.

It was moved, seconded, and passed that the request of Albert E. DelPalacio. Jr. for a waiver of a portion of his Intern hours requirement be granted.

The following Pharmacy Assistant training programs presented by Hr. Palmer were approved by the Board: 335

THE_FOURAUNDRED_AND_FORTY,FIFTH MEETING_OF_THE_WASHINGTON STATE BOARD OF PHARMACY

September 16 and 17, 1982

Burien Police Department 14905 6th Avenue SW Burien WA 9:10 a.m.

Present: Board Members

Lars_Hennum Chairman Harold F. Osborne_ Vice Chairman Joseph_JThoMPaon David Palmer Dr. Arthur Zoloth Donald H. Williams Executive Secretary Joyce Roper Assistant Attorney General Mary-Helen Hansen Clerk

Tbe_buard discussed a Ietter_written_by_Assistant_Attorney General Barbara Phillips t6 De; Eduard J;_HannityDPAconcerning statute RCW 69.41.120 which required all written Prescriptions -to contain two signature lines.Dr. Zoloth suggested that the Board reviewjgeneric substitution prescription blanks - that this portion of thu lew be reviewed to allow doctors to add own method of choice of the drug to be di penned.- Mr. Williams was asked to ask the Medical Association for input re- cording the generic substitution lines for possible revision during the present le,4islative session, with a copy of the letter to the physicians that have com- plained to the Board.

It was moved; seconded, and passed that the following requests be granted:

-- Lisa A. Speigelber& Bellevue WA - Interrship creditfor special project -with the Health Care Financing Administration, Mike Kopcho nen, Supervisor.

-- Ann Donnelly, Anaheim Hills CA - request for Iicensure by taking the law exam, approvaI_of experience as a pharmacist_in Canada._ Ms. Donnelly graduated from the University of Washington in_195B_ and COMPInted the written_ portion of the -Full Board examinations And 674 hours of Internship.She is licensed in California.

Ttd Boatd determined that patient profiles records were a part of the prescription i'd0VaS and should be retained by pharmacies for five years.If these are purged from the computer they should be placed on microfiche (RCN 18.64.245).Board intent is to be clarified in regulation WAC 360-16-260, and the time period is to be included. The information should be published in the January Newiletter.

Chairman Hennum requested that the status of pharmacy and pharmacist licenses 336

after the renewal date be made an agenda itemin-October and in November_for in licensee input. Mrs. Phillips has-stated that the grace petied_as_stated statute refers only to the submission -of -the renewal fee withoutpenalty_, and This_will_elso_be published in not t; a grace period fur_license_expiration; the January Newsletter.The regulation should appear under licenses and fees UPC 360-18 to clarify the interpretation. multiple sites were inveIVed: The h&iiJ niS,:OuSed_hespital_Pharmacy licensing where PetentIy, inpatient and outpatient pharmacies must have separatelicenses when not in the same location. It was suggested that a master license_fdra hospital under the Director of Pharmacy with a listingof-sites would_enabIe the_Board_to know where all drugs were being distributed within abeapitaI;__MrKarl Hohen- garter, BPht_Director of Pharmacy Services Swedish Hospital Medical-Center; Seattle WA, discussed his satellite pharmacies and_pharmacist_eperetionsat his hospital. Dr. Zoloth suggested that the Board requestiaSkital_Pharmacistsof the state to draft language_for Beard review and a_formal_regtflationhearing to clarify and define hospital pharmacy licenses. Itwas_suggested that Board Inspectors he trained in inspecting hospital pharmacy sites.

The Board reviewed newly published information onPhenylpropanolamine_and related products that questions the efficacy and safety ofdiet aids._ Me: Osborne Moved__ that the Board hearing. to--place diet aids_in_Orsscription only status. Motion passed. Dr. Raymond Ragland; Metady-JaMeS_Laberatoriesi__ inilndelphia PA, was present for this discussion:Members_asked_for summary of _ - written and_oraIand-oral = regarding PPA;_It_was_requested that a draft re,:ula:ion he prepared fer_infOrMal_hearing in- October.Input is requested from the Medical_ASSOCIatiOn. The.Senate Social_and_Health Services Committee has con- tiirted the 3,74i-a for any information regarding PPA containing dietaids.

Dr. ZOlOth suggested a meeting with the MedicalAssociation to discuss mutual Medical problems: Schedule I status for Quaalude, triplicate peraCtiptiOns_,_ as well as PPA diet aids. Dr. Zoloth shared a-letter from Dr. George Aageard_MD4___ Professor of Pharmacology, UW Medical SChooI. _Dr. Aagaard_is very_Concerned that hypertensive patients may be adversely affected by takingPPA containing diet aids without physicians' superViaidn.

The Board-appruVeu a revised statement containing the newtime frames for sale of Sehedule Tcough_tyrups_as_prepared by -the Washington StatePharmaceutical Assoc- register beeka_UhliI iatiOh. The statement will be sent out with all Schedule V a new_printing of the books is available.This is the statement WhiCh is to be read ty all purchasers at the time of a Schedule V sale.

Mr. Wayne Peterson RPh, Crista Community Center,appeared_before the -Board to discuss stocking of legend drugs (i.e., irrigAtien_selutiOns)_asfloor stock before receipt of a prescriber's order. Mr. Osborne moved_to_allew_Me. Peterson-as-pharmacist to-stock these legend drugs pending review ofDepartment of-Soeial-and-Heal-th Services requiremetita. Motion passed

representing -the Washington State Nurses Association, was Ms. Keck and char d tier concerns regarding nurse dispensing.

The Board expressed interest in a joint healthprofessionaI=MoIti_discipline committee to explore and deal with alcohol and drug_abUbd_inheaIth_pcofessionalsi during committee (Jctober and November. Ms. Keck stated that the RN Association has formed a 337

to inform the Associaticr, members regarding addiction and the handling of personnel. Es. Keck recommended an article in the Apiil issue of the American Journal of Nursing regarding drug use and abuse among nurses.

Mr. Osburne_and Mr. Williams reported on tha budget hearing for the Board of Pharmacy ttat way held in the Orrice Of Financial Management in Olympia the previous day.

It was suggested that the Investigators meeting in December_be held in conjunction with the board meeting scheduled for December .9-10 in Olympia.Investigators will be asked for input on inspections and the inspection process.

Board members reported on meetings they had attended:

Kitsap County Pharmaceutical Association - Members Zoloth and Osborne attended and discussed RN dispensing, Schedule V cough syrups and Dr. komano's report on pharmacist/patient communication.

jlate Pharmacy Association Long Range Planning Committee - David Palmer

brug Abuse Conference, Ellensburg WA - Executive SecretafY Williams participated, speaking onthe Legend Drug Act and the Controlled Substances Act.

Thbuson moved to approve the August Board minutes. Motion passed.

Nr.. Palmtw discussed the role of- the -Board member as convenor in Ad Hoc cummittees. A ,taitTrs.ii and_minute_taker_shou/d be...stlected by committee_members,_and the timetable 1,-,r first draft established. The Board member should assist in setting the :,t,j,:_tives or the committee.

Ch,,rman henfium rec.,ssed the Board meeting at 3:30 p.m.a until the following day

at ,:CO, a.m.

Friday September 17, 1982 9:10 a.m.

,.:hairman Hennum reconvened the September Board meeting in the Burien Police Department c ereuce room. All Board members and staff were present from the previous day.

111Q Loard determined that it would place the triple combination drug - Ephedrine, PhenYlprophnulamine, C:afeine in legend drug status, since the FDA has declared tints crmbination tu.be a new drug._ In_addition to the "look alikes" containing this_cumhinatien_being manuractUred and distributed to resemble legal controlled substance- products; some_companies_are attempting_ to avoid State laws by placing !.:,ts combination in a form which. does_ not look like a controlled substance. Chaxman Hennum asked that an emergency regulation be prepared by staff for the ,:).:LoDer Board meetin.

The !:.),,m!net in Cloned Session from 9:10 a.m. to 9:20 a.m. to review and sign disciplinary orders. 338

THE_FOURAINDRED_AND_TORTY,SIXIII MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

October 14 and 15, 1982

Burien Police Department (King County Precinct 4) 149056th Avenue SW Burien, Washington 98166

Present: Board Members

LarsAleanum Chairman Harold F. Osborne_ Vice Chairman Joseph J. Thompson David M. Palmer Dr. Arthur Zoloth

Donald H. Williams Executive Secretary Barbara Phillips Assistant Attorney Gcneral (Thursday) tiusan Jensen Assistant Attorney General (Friday) Mary-Helen Hansen Clerk

The Board considered a request from_Mr. Chia,Yao_Hun8;Oklahoma City OK; for approval Of his clinical_experience as internship credit.Mr. Hung is a graduate of the School of Pharmacy at Taipei Medical College, Taiwan.He will receive an M.S. degree in Nuclear Pharmacy from the University of Ok- lahoma in October and will be permitted to take the NABPLEX examinations in Washington in 1983. thrGsborne-moved-to-aIlow-7-1-2-liours-credit for Mr. Hung's 04-0-cal-experience. Motion passed.

Dr. Dale Christensen jobrd Board meMbers in -a discussion of proposed new section Monitoring of-Drug Therapy (definitions),The Board was concerted that the hoard scope -of laboratory tests Include but not_be limited to analysis of body fluids, antibiotic sensitivities,_drug_levels; etc. Further discussion of this proposed section will be held at the November meeting.

The Board reviewed tne Schedule V purchases and letter from Mr. Don Fadden regarding his medical condition, and letter from pharmacist Vicky McFarlane, Holiday Pharmacy, Seattle WA. It was felt that Mr. Fadden's condition should be reviewed by a physician and his medication be by prescription only. P-r-e-ired-te-grant-the request of Ken Robbins RPh, Pendleton OR, that his practice of-pharmacy as a pharmacist licensed-in Idaho be accepted_ at internship. Motion passed. Mr. Robbins passed the NABPLEX examinations in Washington in Jan- airy 1982.

Mr. Osborne moved to accept the petition of_William Mark_Norris RPhi_Tacoma WA, that his work in_pharmaceutical_sales_be_considered_activepractice_of pharmacy, Motion_passed. _Mr. Norris has applied for reciprocity of his pharmacist license to Washington State.

342 339

Mr. Osborne moved_to_approve the request of Mrs. Billie A Kutzera RPh(inactive)_ that she be certified as a Level A Pharmacy Assistant.No further training will be required. Motion passed.

Droltrth-sloved-to-approve-the Continuing Education credits of Roderick_L._New- land RI'h, irt of his Washington State pharmacis-t-iieense. Motion passed.

The Board welcomed Robert Coe MD,-Washington State Medical Disciplinary Board, who is liaison member for the Board of Pharmacy. Dr. Coo was briefed on the proposed new section Monitoring of Drug Therapy.

The Board agreed to continue the reinstatement- inquiry of Dale M. Robinson, pharmacist, Indianapolis IN, regarding his Continuing Education requirements, and ask :or a record of CE hours completed.

The Board discussed the following proposals prepared by Mrs. Phillips at Board request:

-- Quaalude as Schedule I drug - Mr.--Osborne-moved to accept advice of counsel Aanntrnalvd Substc-iren-SI:onaaIndehedule-I-. Motion passed. Dr. Zoloth manufacturing be asked to comment and that the State Medical Association be notified.

-- TripleCombination as Legend Drug (Ephedrine/Phenylpropanolamine/Caffeine) AAG Phillips_recommended_no_action_as Ephedrine was now a Legend Drug (WAC 360-32-050 and -055).The Board agreed.

Phenylpropanolamine (PPA) as Legend Drug - The Board summarized information and hearings to date for Dr. Coe. Attorney BeckeBogard, Seattle WAS representing The Proprietary Association of Washington, D.C., and Dr. Raymond Ragland, Menley-James Laboratories, Philadelphia PA, reaffirmed safety and efficacy of the diet aid products when taken as directed as shown in tests and studies. Dr. Zoloth requested that a Task Force be convened to review all accumulated material and make recommendations to the Board. The Board is concerned with tonicity -and the potential fel* harmfUl effect. Mr. Os- borne moved toproceed with the Task Force_and_asked_for Board members and staff to provide names of personS that would give a_fair_and Onairepraten- tation of interested parties; Motion passed. The Task Force Should indlUde medical practitioners,_The Proprietary_Association, an independent pharma- cisti a Board memberi and_representatives_of_consumer_groups: The Board__ asked that the report be ready for the January Board meeting; with possible formal regulation hearing at the February Board meeting.

WAC 360-18-010 Licensing - ed- role-to-a-regulat-ion-hearing. Motion passed. The amendment would clarify that licenses expire on the date given, and the grace period applies only to the penalty fee. This will be scheduled for a formal hearing at the OeceMber Board meeting and placed on the November Board meeting agenda far discussion.

WAC 360,167260_Patient_medication Record_System ,_Mr: Osborne moved for a Dec,mber regulation hearing. Motion passed. This proposal would amend

343 klt 340

Auring a four year period beginning from the latter end of the one year suspvnsion served pursuant to this Oruer, or the completion of any sentence of confinement arising out of the violations set forth above.

It is further ordered that prior-to the-return of his license to practice pharmacy, James Lee Clancy RPh, shaIltake_and pass -the jurisprudence examination given by -the Board; and that_he_ shall complete .a drug. abhse_program_approved_by_the Board;_and_that he shall provide in the Board a closing report from the drug abuse program and a report from another clinical psychologist or psychia- trist trained in substance abuse, each of which shall indicate that :n his or her opinion the return of James Lee Clancy to the practice of pharmacy would neither endanger the public nor lead to a recurrence ,f he events which brought this matter before the Board.

The Board requested_that.the Assistant Attorney_OeneraI presenting these .disci- :Atrary cases, scheduIe_them Closer_together; for example, 9:00 a.m. and 10:00 a.m., or az soon thereafter as possible.

Zoloth shared a letter from an attorney, whose client is scheduled for a disciplinary hearing at the November Board meeting, asking that the Board not publicize the disciplinary decision, that such publication might jeopardize hIs client's current employment. The pharmacist in question has voluntarily udrrendered his license to practice. The Board determined that they would publish all and any actions or punishments for the good of the profession.

Chief Inspector Charles James winattendthe_Computer_Ad_Hoc_Committee meeting so that eoard inspectors will be aware of the committee's actions.

The Board discussed possible members for the PPA Task Force. Names suggested wre Juhn Chase MD, - retired Dean of the UW Medical School, Alan E Bourse MD, 0corge Aagaard MD, a representative of The Proprietary Association, John Big- elw, an endocrinologist, a psychologist, a toxicologist, Bennett Anderson RPh, an educator, and a representative consumer with a weight problem.

The Board commended two publications as useful resources for pharmacists: the two 'volume edition of the USPDI and the patient infOrmatiOn_bOOkIet published PHARMEX. It was suggested that these be mentioned in a future Newsletter.

Williams. and_ the Board reviewed the Executive Secretary Policies and made the following determinations:

1. Policy Statements - retain 2. Administrative Responsibility - repeal 3. Vehicle Usage - retain, include overall vehicle policy 4. Continuing Education for Investigators -- repeal 5. Conflict of Interest_- revise. Dr. ZoIoth expressed concerns about updating skiIII. 6; Witness Must be_Present_, retain 7. Barrative_Report_Required - place on agenda for Board meeting with Investigators:, possible use of pass/fail rating system. b. Per Diem for Drug Investigators - check with OFM 9. License Checks - combine with inspection process. 10. Compensatory Time - retain

344 341

THE FOUR HUNDRED AND FORTY-SEVENTH MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

November 18 and 19, 1982

Ridpath Hotel Arcade Room W 515 Sprague Avenue SpokaneWA

1:05 p.m. OPEN MEETING

Preseht: Board Members

Lars_bennum Chairman, HaroId_F.OSborne Vice-Chairman David_H. Palmer___ .:oseph J. Thompson Jr. Arthur Zoloth

Lcnald H. Williams Executive Secretary Barbara Phillips Assistant Attorney General ary-Helen Hansen Clerk WIlIard Zcott Investigator

Inv Board discussed the status of the PhenyIpropanoIamine Task Force.Dr. John Chase has agreed to serve;_but_not_to_chair;Dr. Aagaard win review the information and then make a decision. Additional names were_ suggested. Attorney Rebecca Bogard, representing the OTC manufacturers of diet_aids,_and Dr; Ray, mond Ragland, Henley -James Labs, who were present for the discussiOni suggested that Albert C. Eckian, M.D., Florida, be contacted to represent their clients on the Task Force. Dr. Zoloth will represent the Board Task Force members will hold ao organizational meeting after reviewing the. material with regard to RCW 69.41.075 toxicity and safety. Dick Sherwood, Director of Pharmacy for Sacred Heart Medical Center, Spokane WA, reported on recent PPA related emergen- cies in his hospitaI._,The_Board requested that the following agencies or groups be contacted;_ sheriff!s_offices,_SChoOI districts, associations of school counselors, and county health districts_around the state for information concerning abuse of PPA diet aids in schools or with teenagers.

The board reviewed correspondence from drug manufacturer Merck Sharp 4 Dshme advising that RedisoIR Tablets would no longer be sold in Washington State. The tablets were too soft for imprinting.

Information from Bob Rogers of Upjohn indicates that Upjohn's temporary exemption imurinting dates are being met.

The following licensee requests were considered and accepted or denied by motion:

- Depinder Crewel, Auburn WAS internship waiver request. 600 heurs_Internship credit granted provided he document his pharmacy experience in England. 342

eported-on tto meetiog_with theRN Dispensing Committee on 11-1,1-82. 'fl:ri; :oil a_ccmmittee.fro'n_Lhe Nuroest Association are gathering data concerning rw,.(1 and availacility of pharmacy service:' in the state. Data rhculd be 1:aly for a 'anuary 10,1982, meeting in the board of Nursing office::.

2PN regulations may allow Chi's with prescriptive authority who are registure..! ..h 'ne (rug Enforcerent Administration and the board of Pharmacy to prescribe V CxoToiled Substances.The RN board did not make "indicated_use" a f6r the prescription document. The Board of Pharmacy testified atai:.st the deleting of this reinlrement, lib's felt it Was_a standara_of good practac(:, but since. other tresCriLers did not need to_put the_iodicated_use_ora the pgecription, they shru:u not be required to, Huard members suggested that ard tA. Nursing circula:n the new C-.2 regulations to offset abuser activity.

Aw; Philiits saigestci aiU.:ption or a proposed amendment to WAC 360-36-010 on an fmoi,.edcy basis with fe.4ulations adopted on a permanent basis laterto establish tees for I.:Luc...lug CHN's to rreacrite Controlled Substances.

fr. Zoluth moved to adopt _WW.: 360-36-01J sub (2) adding new sections (k) and_fIl___ an dralled by 1..1J. Philliunt.to allow for_Board_regiltratiCt and licensing Of frencriptiVe authority to prescribe Schedule V Controlled Substances.Motion a,sed.

';;AC don-':t-010, sub (2)

$15.00 for application for Certifiea Registered Nurse with pres-riptive authorization; (1) $10.00 for tne annual renewal for Certified Registered Nurse wi'n nr,wriptive authorisation.

Ine tuting recessed at 4:15.p.m. until 7:00 p.m. for a right meeting with Cp6,ane ifamaceutical Association;

Chairman Hei:.ri reconvened the evening meeting at. 7:20 p.m. All Board members ,,rd st..;': were prezeht. Chairman. Hennum asked for a moment of silence for Phama- cist non Katterman of Seattle WA, past president of WSPA, who died that morning.

Osb,ne reported on the new drug approval process of the_F0A,_due to take eriecl next spring. -lte new process.shouId speed up processing of applications, provide better survelfience, and permit approval and review of foreign drugs originally introiucea in a foreign country.

.r, f.oauth urolartied previous board discussion concerning PPA containing dint aids int f.ok alixes aad the formation or the IPA Task Force and a second area of con- hspitalpharmacy licensing problems and possible resolution - for the bene- if. of the Synkane pharmacists.

and Chairman Hei:num gave an overview of the Sunset review and raniri- AL,u for the Board anu the practice of pharmacy.

rreocribiNg, C-V sales, andr.armacist prescriptive authority were subjects ..ceiewed for the audience. 343

THE_FOUR_HUNDRED_AND_FORTY,EIGHTH MEETING .0F_THE_HASHINGTON STATE BOARD OF PHARMACY

WEA Building - 319 E. 7th Avenue Olympia, Washington 98504

December 9 -10, 1982

Board Members:

Lars Hennum Chairman_ Harold F. Osborne Vice-Chairman David H. Palmer Joseph J. Thompson Jr. Arthur Zoloth

Staff:

Donald H. Williams Executive Secretary Barbara_Hhinipa AAO; Counsel to the Board Mary,BeIen_Hansen Clerk Board Investigators David CampbellCharlesJames, Frank Bracelin, Willard Scott, Robert Miller, Richard Morrison, Hobart Ashmore Susan Masters Intern Desk

Hay Olson Executive Director, Washington State Pharmaceutical Assn.

9:30 .1.m. CLOSED SESSIONMeeting With Board Investigators

II:co a.;-:1 OPEN MEETING

Coe Board Jeni,,d a request by Ms. Sean Kelleher RPh (Wisconsin), Yakima WA, for transfer of NABPLEX scores. Wisconsin did not forward her scores in response to a request by the Washington Board.Mt. Kelleher is prepared to take the Full iloarus in January 1983.

Greg Hovander RPh, Valley View Clinical Pharmacists,_Monroe WA,__presented a proposed protocol for the distribution of drup_by nurses,Mr, Novander discussed possible licensing and approval for pharmacists to enter into a contractual agreement and run as a_satellite pharmacy any kind of formal setting where a Regis- tered Nurse i9 distributing drugs. No Controlled Substances would be prepackaged and stocked. The RN would be serving as the pharmacist's agent. Places (A' distribution would exist only where no other pharmacy services were located within ten miles of that site. The Board will review Mr. Hovander's protocol for procedures applicable to resolution or the RN dispensing issue now under discussion with the RN Board.

ChJirman Hennum opened the FormaI Regulation Hearing at 1:00 p.m. 344

WAC 360-40-060 Submission of Condoms for Testing. New Section

Or. Palmer moved to adopt. Motion passed.

WIC 360-40-070 Cotdom Testing. New Section

Mr. Osborne moved to adopt. Motion passed.

WAC 360-40-080 Suspension or Revocation of Prophylactic Licenses.New Section

Mr. Osborne moved tor-adopt. Motion passed.

4; 360-44-020 Derinitions (Public Records Disclosure)

Err Hsborne moved to adopt as amended. Motion passed.

WAC 360-44-040 Operations and Procedures.

Er. Osborne moved to adopt as amendcd.Motion passed.

WAC 36U-44-090 Copying.

;.;n. Osborne moved not to adopt the proposed amendment. Motion passed.

Attachment 1. WSR 82-22-087Notice of Intent to Adopt, filed 11/3/82

,:ttachment 2. WSR 83-07-083Rules Adopted, filed 12/17/82

End of Regulation Hearing

Williams reviewed the stvtus or Schedule V cough syrup salen since the new reeulations were adopted: PbArmacies_are_sending in the single register sheets as required; there does seem to be a reduction in sales by many pharmacies. Mr. HEy Often, WSPA,_offered to supply monthly statistics from the sales of books by hiP_offiCe. It was also suggested that new books might have 10 lines to a page thstead of the present 20. The Board requested statistics on the C-V sales by high volume pharmacies.

Eask-Ferce Mr. Williams reported that_ a packet of_information_has_been pre - pared for all members. All information -is to -be Channeled- through the Board orrice. John Bigelow, -Wayne Kradjan lift;_and_Bennett_AndersON RPh have accepted appointments to the Task Force. "Cook alike" advertising received in .the board office ho longer lists PPA as at_ingredient; just ephedrine and caffeine since theFDA ta5 .:CItIaWed the triple combination.

C:,mheter Recolations Task Force - Or. Palmer reported that he was pleased with the p,mress or the committee, and that they were probably two to threemonths away 3-5

THE_FOUR_HONDRED_AND_FIFTYFIRST MEETING_OF_THE_WASHINGTON STATE BOARD OF PHARMACY

March 16 and 17i 1983

KingCountyPrecinct 4 14905 6th Avenue SW Burien, Washington

Board Members Present:

Lars Hennum,-Chairman Harold_F._Osborne, Vice-Chairman DaVid. Palmer__ Joseph J. Thompson Dr. Arthur Zoloth

Staff; bonald H. Williams, Executive Secretary_ _ Jeffrey O. C. Lane,_Assistant Attorney General Mary-Helen Hansen, Clerk

Others:

Mel Gaumer, Menley and James Laboratories Jeff Smithi Washington State Medical Association Becky Bogard, Thompson Medical Company .ban Cohee Herk DesForres, Payless NW Karl Hohengarten, Swedish Hospital Doug Meeman, Group Health Holly Streeter,- Washington -State Pharmaceutical_AssoCiation Kathy Moritis, RN, Washington State Nurses Association

The meeting was opened at 9:20 a.m. by Acting Chairman Harold Osborne.

Board Member Reports

1. PPA Task Force - Dr. Zoloth

More testimony is neededi_public hearings should be held, and a procedure fer_reviewing the volume of data developed. A chairman should be selected before the first meeting to enable Task Force members to begin deliberations at once.A representative of the- high school counselors group is needed. Lobbyist Becky Bogard_wiII represent Thompson Medical. Menley ana James Laboratories win be represented by Mel Gaumer. Other members include: -Drs. Chase, _ Aagaard, Eckian, and Robertson; Pharmacists Evelyn Benson_or_Bennett Anderson and Wayne Kradjan; and_John Bigelow, retired Executive Director of the State Hospital Association.

49 346

CJpiet of a new report regarding toxicity were requested. Staff was directed to fc.rmalixe the Task Force and set the first meeting. Dr. Zoloth agreed to act as convenor and represent the Board.

Tht Board reviewed a letter from John Morgan, MD.,-Medical Professor and Director at the Pharmacology Program, Sophie Davis School or Biomedical Education, City CoIlege_of New YOrk. Dr. Morean objected to the Board minutes or June_24, 1982; reporting his- presentation on "Iook,elikee before_the Board. Dr. Morgan's letter will be made available_Wthe Task Force. Dr. Zoloth moved to move on to another topic. Motion passed. The Task Force will be made aware of the board's actions and that the 1,:tter was given full consideration.

Joe Thompson submitted a report of the November 9, 1982, meeting of the CE Committee prepared by Sharon Sullivan RPh. Chairman. The-Committee recommended changes to the prPsent system of approving CE programs, asked for more participation by Hoard members, and the appointment of new hospital pharmacy representatives.

lhe Board will provide guidelines to the Committee and review the membership, appointing new members as needed. Joe Thompson and Don Williams will review the report and the membership.The procedures For .20 day prior approval of CE programs was suggested as a NEWSLETTER item.

.3. Poard Regulations and Drug Recall - Art ZOIOth

Changes should be made :1.n WAC 360-16-150 to allow_ Pharmacists to accept drugs_For return to manufacturers during a national recall, and to permit uuused medications in unit dose pachages to be returned to pharmacies for creait where the unit of use has not gone out or the control of individuals either dispensing or administering.

Dr,Zoloth moved that AAC-Lane prepare an emergency regulation amendment to WAC 360-16-150 for the April Board meeting With permanent adcption to be filed for early hearing.Maslen passed:

L4w7. Hennum arrived at 9:55 a.m. and assumed the Chair.

4. Ad Hoc Group, Drug Diversion and Substance in- Inst#tutions

Dr. Zoloth is convening a meeting of representatives from the medical and RN disciplinary boards, DEA, hospital administration, and the State Hospital Association, employee assistance programs, and the legal department of the State Medical Association to discuss_the problem and.to form a committee for study and education that woUId prepare a forma/ set of guidelines for reporting_and referral.It was suggested that the WashingtonState_Pharmapeutical Association be contacted to send a repreSentative as they_have begun an impaired pharmacist program. Rob Menauli State Hospital Association, will coordinate the program. Don Williams will attend the March 24, 1983, meeting.

TheBoardrequeated an update on substance abuse for a future meeting. 347

THE FOUR HUNDRED AND FIFTY-SECOND MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

April 20 And 21; 1983

King County_Precinet 4 14905 6th Avenue SW Darien, Washington98168

Pnard MeMbers Present:

Harold FUsborne Chairman David -H. PalMeri_Vice-Chairman Joseph J. Thompson Dr. Arthur Zoloth Lars Bennum

Staff:

Donald H. Williams, Executive Secretary Barr+ara Phillips, Assistant Attorney General Mary-Helen Hansen; Clerk

Others: See attached list

The four hundred and fifty-second meeting of the Washington_State Board of Pharmacy was called to order at 9:05 a.m. by Chairman Harold F. Osborne. In opening remarks as newly elected Chairman, Mr. Osborne reviewed the recent accomplishments of the Board and the goals and challenges it faces today, icludinL the Sunset review by the Legislative Budget Committee.

9:15 a.m. Chairman Osborne opened the Formal RegnIatory Hearing:

Notice is hereby given in accordance with the provisions of RCW 34.04.D25 that the Washington State Board of Pharmacy intends to adopt; amend; or repeal rules concerning:

Adding New Sections WAC 360-12-150, 360-13-100, 360-16-300; adding New Chapter 360-33 WAC, 360-33-050; and repealing 360-23-040.

110._WSR 83-06-074 was filed with the code reviser March 2; 1983-;

WAC 360-13-100 Provisions for Continuity of Drug Therapy for Residents WaS cousrdered by the Board.

The following persons testified byfore the Board:

-- Fran Moellman,_Manager, Operations Program, Bureau of Nursing Home Affairs/DSO, case.tpia CON

-- Sandie Beeman RPh; Washington State Pharmaceutical AssiotionPRO

351 348

',4AC Jo0-21 -u4d is hereby reidIed. Attachment #6

End of Regulatory Hearing

Pnenylpropanolamin,

Leonard Albert, mD,Ph:D.(PhattatoIogy4._MPH,related hisexperience knoWledge of_adf:erSe reactions tO_PhenYiPrepanolamine, andhis concern With the.OTC otatUs_Of PVA._ Dr._Albertfelt that PPA should be a achedeled drug-with controlled_ prescribing such asthe laws enacted ':or amphetamines. Dr. Albert has egreed to serve on the PPA Task FOrce:

III: PPA Task Force

Task Force nominees are to be contacted and_ameeting_date set. The Board requested that the Teak FOrce_report bythejuly Board meeting. The Chairmae shOUId be seIetted_before_the firstmeeting.The Task Foree is he be given_copies_of_the statute. Terms used in the statute are.Mandatory_on_what_the_Beard shall consider and what thedeterminatiOn Shall be based on. Efficacy may be considered but would not be- enough under the statute for the Board to place PPAin prescriptioe OnIy_status, according to Barbara Phillips, AAG. Consumer repreSentation_is_still needed, and a physician who has actually- treatedpatients for weight control would be a wise addition to the TaskForce.

is Not IV. Pharmacy Assistants in a Hospital Pharmacy-WhilethePharmacist went - Valley General Hospital, Monoe WA.

SteVe Erickson HPh, Director of Pharmacy, CarolJohnson HP4; AIvina_ Hereth_HN/Director of Nursing Services, and LandBaVitth, Hospital Ad!! minist-ator; explained hospital procedures and pharmacistavailability to the pharmacy site. procedure with reg rd The Board deterrained that the_present_supervision Hospital pharmacy is not in to Pharmacy Assistanta_at_VaIIey General violation of WAC 360-52-010:

Dr. ZOIOth moved that_the__"C" Grade be removedand the Inspection continue Under JCH rules. Motion passed.

If a similar situation occurs during ahospital pharmacy_ inspection;_ Boar! Inspectors are to be asked te_bring thematter_to_the Board and provide a copy of the most recent JCH report on thehospital.

V. Substance Meeting - Don Williams

RepreSentatives of the health professions and hospitaladministratiOn Were made aware of the extent of the problem anddiscussed Way; to 349

THE FOUR HUNDRED AND FIFTY-THIRD MEETING OF THE WASHINGTON STATE BOARD OF PHARMACY

May 11-12; 1983

Conference Room Mason Clinic East 13014 - 120th NE Kirkland WA board Members Present:

David_ H. Palmer, Acting Chairman Jonnpli.J. Thompson Le. Arthur Zoloth Lars Hennum

Ucrald H. Williams, Executive Secretary harbara Phillips, Assistant Attorney General, Cc nsel Mary-Helen Hansen, Clerk others: See attached list

The-four tundred_and_rifty,third meeting of the_'4ashington State Board of Pharmacy was called to order at 9:08 a.m. by Actin Chairman David R. Palmer.

School of Pharmacy, Universi4 of Wasuington - LynnBrady, Ph.D., Director, Academic and Student Programs

The new curriculum allows for flexible choices or eAternships. Didactic, required courses are scheduled ror the :ist two years and electives are scheduled for the third year. The basic philosophy has not changed. Board members stressed the heed for the following:

1) A required law class in the spring term at the end of the pharmacy studies program to present the new laws and regulations enacted and to prepare students for the Jurisprudence Examination.

2) Nore-inVolVement by Board members and staff with students and curriculum, seminars, lectures, etc.

Importahce_of_the_behavioral science course to prepare students for contact_with the public. Student development is weak in this area, particularly with regard to community pharmacy. A possible change in the time this class was offered in the curriculum was suggested.

4) Better communications and contact with curriculum and intelnship programs at the Collegeor Pharmacy, Washington State University.

353

27-436 0 - 84 - 23 350

_ Washington State. universityCollegaof Pharmacy will beasked L6 Mdke j presentation on their pharmacy program ata filture Board meeting.

E:Lergency_Gntpatient-ffeeieation/Proposed Regulation William Baluec .,:nior Pharmacist, Harlorview Medical Center, and-Spokesman for the Pro- lessienalAffairs Council, The Washington StateSociety of Hospital hdrmaiicts.

. . Tr,, proposed rcrodlation would be- placed in chapterWAC 360 -17 Hospital Ph.wmacy JtundarM,_jKA would_allow_the_pharmacy tomaintain control of mAest aldeOhta of_prepackaged medication fordispensing after haurs. It IL modaIed_after the State of Oregon regulations onthis topic; Tlie proposed. regulation would allow 1,11 dispensingin-emergendy.roots after hours and provide a controlled system Ofmedidine distribution. _ for rerlatery .r. Eoloth tikiov that the draft regulation te-preimired :r_ariag-hefore the Board at the Julymeeting. Motion passed:

It was suggeSted_that_the The committee-Was cempl:mented onits work. Nurses group for an expression of committee- Contact the Emergency Room their needs; before final draft wassubmitted.

Sandia beetmut, RPh, reported thatthe Interprofessional Affairs Com:little, ASSociationi_hadnot addressed the prob- Washington State Pharmaceutical and_suggested that the Board look at that lem of Controlled Substandea of the state sad federal regula- aroa at the regulatiOn_heaeingi_because tions regarding Controlled Substances.

Art Zoloth II:. PTA Task Force - Initial Meeting - Hospital. It, ZOlOth reported on thepreliminary meeting_at_Virginia_Mason Executive Director of the StateHospital Associa- Me, John Bigelow; retired met tion; who will Chair the TaskForce, Len Alberti_MDiand Don Williams organization. -.of the_Task Force andinformational with him to ',fork out the __The_focus of the review will be safety: data t.:v would be asked toreview: ad-rules giving authority to theBoard to Jon Williams will read the laws Task Fordo members act in tnis matter. It was the_consensus of the present that there may be a conflictof interest for Dr. ECkian; whose manufacturers of diet_aids_, to remain expenses Weee being paid by the OTC witness in- Force. He should appear aS_an expert as ,t member of the Task suggestion on behalf of Menley and Stead: lire Gaumer objected to this James Laboratories. the Board-reinforce its previous Aftsr discussion, Mr. HennUM mfted_that Motion paased. stat,nrcrIL that Dr.-EFkian be a partof the-Task Force. May 26, 1983, at Virginia Mason The first full Meeting_will be held on Hospital, Seattle; beginning at 7:00 p.m. Times Don Williams reported that a study ondiet MO conducted by Pharmacy Medical seetiS to be the basis for thecurrent TV_ad9ertisement_by Thompson DexatriMR than_any_other product. 3000 that_more pharmacists recommend DexatrimR, pharmacists were surveyed, 807responded; 20.8% recommended recommended nothing. 24% 9.2% rece0Melided-Diatack _10.4% not recomenCDemit0 answer. TIMP(8 tiobxeftWPharosoistsAtd number of adverse comments to this The Board_Office_has received a T.Y. advertisement. report according to Dr. Zoloth: PPA is also showing up Oh th011111N 351

APPENDIX 3

SUBMITTED FOR THE RECORD

THE FOOD AND DRUG ADMINISTRATION

PUBLIC HEALTH SERVICE

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOR THE HEARING BEFORE THE

SUBCOMMITTEE ON HEATH AND LONG-TERM CARE

SELECT COMMITTEE ON AGING

HOUSE OF REPRESENTATIVES

JULY 2Ii 1983 352

The following statement is provided for therecord of the hearing of the SUbCOMMittee on Health and tong-TermCare; Select Committee on

Aging; U.S. House of Representatives, July21; 1983; We also presented testimony at a joint hearing before the Houseand Senate Aging

Committees on June 28, 1983 on the more generalsubject of the safe use of drugs in older Atericans.

OTC-DrUu-RAV-i-e4

We were requested by the Subcommittee staffto distUSS our over-the-counter (OTC) drug review process; thedrug ingredient phenylpropanalomine (PPA) and our adverse drUg reaction(ADR) reporting

United system. OTC drugs are an important part of health care in the

States affecting the elderly as well as the generalpopulation. These drugs provide consumers with products forthe treatment of minor

Conditions without the need for costly medicalservices. Because they may be used without medical supervision;it is essential that OTC drugs not only be generally recognized as safeand effectiVe, bUt also that they provide adequate directions for use topermit consumers to realize their benefits without significant risk of adversetide effettS. In

1972, Food and Drug Administration (FDA) established the

Over- the - counter drug review to assurethat OTC products, then on the market; or introduced in the future, meet thesestandards of safety and effectiveness; 353

Before the establishment of the OTC drug reviewi there hadnever been

an evaluation of the available scientific evidence to demonstrate

safety and effectiveness for most OTC drugs. Prior to passage of the

1962 amendments to the Federal Fodd, Drug, and Cosmetic Act which

established the legal obligation to demonstrate effectiveness; drugt

entering the marketplace needed only to be shown to be safe. Before

1962, most OTC products were marketed without prior Agency clearance

because it was assumed that OTC drugs did not pose significant safety

problems and were, therefore; generally recognized as safe; FDA

regulated OTC drugs mainly through cowl actions against specific products using the statutory prohibiCons against misbranding and adulteration; However; this approach was found inadequate to bring about systematic application of the effectiveness provisions of the

1962 amendments to the estimated 300,000 marketed OTC products with annual sales of nearly four billion dollars. In its application of the

1962 effectiveness amendments, FDA was assisted by the National

Research Council of the National Academy of Sciences; Beginning in

1966; the Council evaluated about 4,000 products, including 512 OTC drug products that FDA had approved for marketing on the basis of safety only. About 300 of these OTC prdducts were found to be ineffective for one or more of their labeled uses; FDA decided it was time to take a further look at t?': OTC marketplace.

357 354

In dedding how to conduct the OTC drug review, theAgency had two by choices: It could review each of the OTC products individually and, separate court actions; move against each violative product, a process that would take at least several decades to complete; evenif the market remained static and new products did not enter themarket. Or it could establish rulemaking procedures to write monographs for each therapeutic class of OTC drugs; Because it was estimated that there were only about 500 active drug ingredientscontained in OTC drug

products, the Agency decided that rulemaking by active drugingredients

within therapeutic classes would be the most cost effettiVe,efficient;

and equitable procedoee

The review began in 1972 with all OTC drugs beingclassified into 25

therapeutic categories (e.g., antacids, laxatives); and two

mistellanebUS categories; The OTC drug review program is a three-phase

rulemaking process culminating in the establishtent of standardsfor

the different nonprescription therapeutic drugcategories. The first

phase was accomplished by advisory review panelt, eachof which

included as voting members a pharmacist; a pharmacologist or

toxicologist; phycians, and other scientifically qualified

individuals, as well as nonvoting technical liaison members 355

representing consumer and drug industry interests. The panels were

charged with reviewing the ingredients in nonprescription drug products

to determine whether these ingredients could be generally recognizedas

safe and effective for use in self-treatment. They were also charged

with reviewing claims and recommending aporopriate labeling, including

therapeutic indications; dosage instructions; and warnings about side

effects and preventing misuse.

According to the terms of the review; the panels classified

ingredients in three categories as follows:

Category I- Generally recognized as safe and effective for the

claimed therapeutic indications;

Category II- - Not generally recognize safe ana effective or

unacceptable indications;

Category III - Insufficient data available to 2ermit final classifications.

Based on the information received; and on the expertise of the

panelists and on their deliberations* each panel prepared one or more

reports to the Commissioner containing its conclusions and

359

it k1 356 recommend-Atli:int, including a proposedmonograph Wtith describes the ciiuitions under which a drug isconsidered safe and effective and properly labeled for OTC use; Thereafter; the Commissioner then monograph in the Federal Register publishes each report and recommended public as an Advarite Witice ofProposed Rulemaking; and invites panel reports are published comment; Under FDA's OTC procedures, special exactly as received. If a report involves an issue of

significance; FDA's views are expressedin the preamble to the report.

After review of the public comments; atentative final monograph- -the

second phase -- proposed rule) ispublished with opportunity for further The public comment and Oral argumentbefore the Commissioner.

publitation of final regulations inthe form of drug monographs is the

third and last phase of thereview process.

of The panel phase of the OTCdrug review extended over a OetiOd individuals participating in this almost 10 years; with over 300 held in February unprecedented projett; The first panel meeting was

1972; by the panel convened toreview nonprescription antacid October 1981, at Which time ingredients. The latt meeting convened in ingredients for miscellaneous internal the panel charged with reviewing Between 1972 and 1981; use finished itsreview of menstrual products. effectiveness of an initial determination wasmade of the safety and ranging from antiflatulentt to ingredients for therapeutic claims

360 357

antimicrobials; and from hair restorers to pinworm remedies; These findings were based on a review of 14,000 volumes of data submitted largely by manufacturers, but also by concerned consumers, pharmacists, and other interested parties. The panel's judgments were also based on their own clinical experience and expertise, on marketing experience of ingredients, and on both controlled and uncontrolled clinical trials.

The panels also relied on the published literature; but isolated case reports, random experience,..testimonialsi and-reports lacking sufficiart AAails to permit scientific evaluation were not

1.. FDA received nearly 60 reports from the panels. These reports and monographs summarizing the panels' recommendations to the

Commissioner of Food and Drugs were published in the Federal

Although the OTC review is -everal years away from completion in terms of ?ire regulations, it has already had an impact on the public's attitude toward self-meuxation and on the marketplace.

Publicity given the review by the news media has resulted in a heightened public awareness of nonprescription drugs and their usefulness in health care. 358

substantial scientific research that The review has also generated has produced impressive amountsof new data on nonprescription drugs;

Approximately one third of the ingredientsreviewed by the panels were

Additional shown to be safe and effective fortheir intended uses. data are being developed on many of theremaining ingredients in an effort to demonstrate their safety oreffectiveness. However; ingredients that cannot be shown to beboth safe and effective for their intended uses have been, and arecontinuing to be, dropped from formulations and will eventually disappearfrom the marketplace.

they A few ingredients were found tohe so unsafe by the panels that were removed from the marketbefore completion Of the full rulemaking recommendations were process. In these special cases; the panels' For published as the Agency's proposals toexpedite market removal; ingredient hexachlorophene was removed from example, the antimicrobial

the nonprescription drug marketin 1972 because of potential neurologic including tribromsalan and toxicity. In 1975, dth-cr antimicrobials;

skill-dr halogenated salicylanilidesthat were found to be

photosensitizing ingredients; were removedfrom the market; and, in

1977, zirconium; widely used inantiperspirantt, was removed from

"aerosolized" drug and cosmetic productsbecause of the Potentia: for

partitOdtt! Zirconium to cause granulomaformation in the lungs. 359

In &and 1979; the Agency initiated a recall of all oral and topical products containing methapyrilene from the OTC market bet-Mite a

National canter, Institute study provided data implicaMg th:s ingredient as a potential human carcinogen.

PPA (Phenylproriamalaratme)-

We are aware that the Subcommittee is especially interested in OTC preparations containing PPA. We would, therefore, like to provide you with batkground information on this drug;

Phenylpropanolamine is available to the public in a number of products. It is available as a prescription drug; and as OTC

editation; in the form of potent stimulants, in the form of cough-cad-allergy preparations and appetite suppressants.

Two different adVisory review panels have made recommendations to the

Agency with respect to PPA. The advisory review panel report on OTC cold; cough, allergy, bronchodilator, and antiasthmaticdrug products was published in the Federal Register ofSeptember 9, 1976 (42 FR

38312). That Panel concluded that PPA and its various salts were

generally recognized as safe and effective(Category I) for oral use as

a nasal decongestant. The panel recommended that the adult dose for

immediate - release dosage forms be 25 mg every 4hours and for

sustained-ralea-7: dosage forms was 50 mg every 8 hours;rot to exceed

363 360

150 mg in 24 hours in either case. The Panel recommended that the drug be administered for no longer than 7 days.

In the Federal Register of October29; 1977 (42 FR 56756) the Agency subsequently deleted from the OTC drug reviewthe provision for a sustained-release preparation. Consistent with Agency policy (21 CFR

200.31) sustained- release dosage formscontaining an amount of active ingredient in excess of what is considered tobe generally recognized as safe in a tingle-immediaterelease dosage unit are regarded as new drugs and require the approval of a newdrug application before marketing.

The tentative final monograph(proposed rulemaking) for nasal

decongestants is currently being developedand is close to completion.

The Agency's conclusions regarding the useof phenylpmpanolaMine in

OTC cough/cold drug products will beinitially presented in that

document.

The OTC Advisr,ry Review Panel onMiscellaneous Internal Drug Products Its also reviewed PPA for its use in OTCweight control drug products.

conclusions were published in the federal-Register of February 26; 1981

Panel to be (47 FR 8466). PPA hydrochloride was judged by the

generally recognized as safe and effettive(Category I) as an appetite

suppressant at a dose of 25 to 50 mgbefore meals 3 times daily With a 361

maximum of 150 mg per day for either immediate-release or sustained-release dosage forms. The Panel also recommended that weight control preparations be used for no loner than 3 months; Prior the

Panel's report, PPA had been available in OTC weight control products

in an immediate-release dose of up to 37;5 mg and a time-release dose of up to 75 mg, with the total daily dose not to exceed 75 mg in either case;

Between the time the panel's report was forwarded to the Agency

(March 1979) and its publication in the'Federal Register (February

1982), the Agency became aware of several reports indicating that

PPA doses higher than thbse currently on the market (but Within the higher range recommended by the panel) cause elevation of blood pressure. The preamble to the published report highlighted these data and also discussed other studies which showed that current marketed dosages produced no such effect. The preamble indicated that further studies were needed to establish a suitable safe dose level for PPA.

The Agency concluded that further studies appeared necessary to determine the extent to which PPA induces hypertension in normotensive patients or aggravates pre-existing hypertension, and whether PPA interacts with aspirin or other similarly acting drugs at the dose levels recommended by the Panel. The Agency concluded that until the safety questions are resolved; PPA would not be permitted to enter the 362

marketplace at dosage levels higher than those currentlyon the mar'44t.

The Agency believes that this position Wat scientificallyjustified by the evidence available at that time;

In response to this controversial issue; theAgency hat received numerous comments on the Advance mntiCe ofProposed Rulemaking and is

in the process of evaluating them. In addition, the Agency iS continuing to monitor any and all available data andinformation on

PPA. Because of the complicated nature of thisissue, the tentative

final monograph for OTC weight control drug productsis some time away

from publication; Resolution of the PPA issue hat also delayed final

processing of the OTC nasal decongestant tentative finalmonograph. If

any new information shows that any of theexisting uses, dosage levels;

or dosage forms of PPA posesafety risks; the Agency will take

appropriate regulatory action;

Post-MarketingSurvei 11ame/Adverse

Reports of adverse drug experiences received by adrug manufacturer

are required, by law and regulation;to be periodically submitted to drugs which are the FOA. These requirements, however, only apply to

the subject of approved new drug applications(NDAs). For the most

part; these are prescription drug prOdUCts; 363

There is no such reporting requirement for OTC drugs since most OTC drugs have not been approved via the new drug approval process. As part of its ongoing program for monitoring the safety of drugs marketed in the United States; the FDA does, however, solicit reports of adverse drug experiences from consumers, physicians and other health professionals. These reports are voluntarily submitted to the FDA, or to a drug manufacturer who, if the drug has an NDA, must then submit them to the FDA where they are evaluated as a potentially emerging-drug-- safety problem. Although underreing is substantial with such voluntary reporting systems, the information available is probably a fairly accurate indication of trends of the incidence of adverse events

With any given drug.

As stated above; the Agency is continuing to monitor all available data and information on phenylpropanolamine. This includes adverse drug reaction reports and other surveillance activities.

Before discussing these; however; we would like to comment beriefly on phenylpropanolamine drug use.

Although precise estimates of actual population exposure to PPA are unavailable because many of these products are purchased OTC and seldom prescribed; data from a variety of sources such as IMS America audits,

Pharmaceutical Data Services and the Michigan/Minnesota Medicaid system suggest that the level of exposure Is considertle; 364

The vOlUritary case reporting program continues to provide reason for concern regarding the safe use of PPA as anOTC drUg. It regains difficult to define the extent and significance of the problem although there are ongoing efforts using FDA contract resources toaddress this area. The FDA is coordinating two studies which are looking at the risk of serious events such as intracranial bleeding, i.e. Stroke, in persons exposed to PPA. One study is being carried out in the

Michigan/Minnesota Medicaid system; the other in the Puget SOUnd HMO.

Results from these stUdies should be available in late 1933;

The Agency is also in the process of funding a study of toxicity of

PPA and other StiMulants in animals, specifically a rat model: The administrative details have not yet been completed, but should be in the coming month, and the investigator should beable to provide data

On the ability of these agents to contribute tosubarachnoid hemorrhage; the major morbid Offett Of PPA.

Thus, we are carefully assessing; and will continue to assess; the complex Is of the safety of this drug. Also, bedaUte of the seriousness of the adverse reactions associated with the use of

PPA products; all of the new data being generated arebeing reviewed by

FDA'S DiVitien of Cardio-Renal Drug Products; whose staff includes 365

specialists in the field of cardiovascular medicine. In addition, should the need arise; this issue could also be taken before that

Division's standing advisory committee on Cardiovascular-Renal

Drugs.

Conclusion

In conclusion, we remain committed to the concept of providing safe and effective medications OTC. It cannot be overemphasized that OTC drugs are vital to the health care system in this country, especially when one considers the rapidly accelerating costs of providing and obtaining adequate medical care.

369

27-436 0 84 24 366

MEDICAL SOCIETY or THE 15%::TE OF NEWVORK 420 LAKEVILLE ROAD LAKE SUCCESS. N.Y. 11042 (1516)488.6100

FOWAROSMGELOAD,--- EXECUTIVEVME.PREWOINT

August 2, 1983

The Honorable George C. Wortley House of Representatives Washington, DC20515

Dear Congressman Wortley:

At its most recent meeting on June 16, 1983, the Council of the Medical Society of the State of NewYork_considered the aangers inherent in the unrestricted sale of pheftylpro-_ _ panolamine hydrochloride in diet-pills or liquida.__The Council; recognizing the great potential for the abuse_of this substance, adopted a resolution which called_for the making of phenylpro- Panolamine hydrochloride a prescription drug and directedthat the New York Congressional Delegation be informed of thisposition.

Please be advised, therefore, that the Medical Society of ;he State of New York supports all appropriate Federal legislation which would make phenylpropanolamine hydrochloride a prescription drug.

We respectfully request, furthermore, on behalf of the_more than 25,000 members of the Medical Societr_of the_Sfate of_Nor York, that you lend your support to Federal ItgisIation_which would make phenylpropanolamine hydrochloride a prescription drug.

Thank you very much for your kind attention in this matter.

Siyferely,

Edwsrd_Siegel, M. Executive Vice-Pre ident

S /H/ 367

THE PROPRIETARY ASSOCIATION 1100 Pennwlvano co Avenue N W /Waylvngf on DC 20006/PhOne (202) 393,1700

August 17, 1983

William Holamendaris Majority Staff Director Subcommittee on Health and Long-Term Care House_ Select _Com_mittee and Aging 715 House Office Building; Annex 1 Washington, D.C.20515 Dear Bill:

_ _Pursuant to our telephone conversation, please find encloseda copy of The Proprietary Association's Statement for inclusion in the offieialhearing record of the Subcommittee's July 21 hearing on '.The Safetyand Efficacy of OTC Drugs." We certainly appreciate this opportunity to provide the Subcommittee with this Statement and hope that the information will behelpful in ita deliberations.

cerelyi

Allan R. Rexinger Director of Legislativeations

Enclosure:Statement of The Proprietary Association

ARRibl

371 090

THE PROM EMY ASSOCIATION 1700 Pennsvivona Avenue, ti it/ Washington. D C 20006/Krone Q021393.1700

Statement of Tile Prcip-rietary AssoftliOn Public Hearing on "The Wity and Efficacy of OTC UMW' Before the Subcommittee on Health and Long-Term Care Select Committee on Aging_ U.S. House of Representatives July IL 1983

Preface The following statement is submitted for inclusion in the officialtearing_record on behalf of The Proprietary ASsetiation; a 102 - year -old tradeassociation; the active members of which are engaged in- the manufacture_and distribution of nonprescription or over-the-counter (OTC) medicines. OTC medicines are intended for use by the consumer for the treatment of minor, generally Self- limiting ailments or disorders, such ns headache, acid indigestion, colds symptoms, minor skin irritations; and so for They include such products as St. Joseph's -.Whine; Vieks Cough Syrupe, Ns. nit Skin Crearne, Tumse, and many others. The Association's - members are subject _to_ the Federal Food, Drug and Cosmetic Adt (21 LUX. 301; at Is.); administered by _the Secretary of Health and Human Services and the Food and Drug Administration.

I. Self-Medicationis-Vital to the Nation's Health Care System Nonprescription medicines are the first line of defense in the nation's total health care system.These products are composed of ingredients -whose pharmacological actions are generally well understood and there is awide margin of safety in their useThey are usu.' by consumers for the treatment of symptoms and illness and injury without the supervision of a healthprOfaliOnM. The food and Drug Administration's Commissioner, Arthur Hull Hayes, Jr.,M.D;, has spoken of the importance of nonprescription medicines: "Nonprescription drugs occupy an essentialplace in health core.The ability of Americans to select, buy and use_over7the-counter products to treat Conditions that do not require the attention of a doctor is,_I believe, a cornerstene _Of our health care system and of our policyfor consumer health protection. Our job, both industry's and FDA's; is to see that_the_ cornerstone remains firmly in place, and that means that the proprietary drug industry needsto maintain its high standard in the quality; manufacture; and marketingof

REPRESOMMGkwarAauRuts 140NPRESCRIPTCN MEDIONE5 369

OTC drugs, and that FDA needs to be both vigilant and efficient in carrying out its responsibilities as the public agency charged with regulating OTC drugs."1 Responsible aelf-_medication performs valuable and even crucial functions for individuals; the health care system, and the economy.For the individual, it is a familiar, inexpensive, and convenient method of treating comm. "scomforta. For the health care system; it provides a _shield agait st a delu visits_to health professionals for minor disorders;For the nittitnal econ .t helps contain the demand for primary care and, in turn; the total cost 01 formal medical services. The U.S. Department of Commerce publication entitled U.S. Industrial Outlook, for example, underscores the significance of OTC medicines in the nation's health care scheme.The statement, true in 1978, has even more validity today. Self-medication with -proprietary drugs is a significant factor in the U.S. health care scheme.Escalating costs of health care create a greater need- for low cost self-medication than ever before.Seventy-five percent of all _illnesses and injuries are initially treated through self-care and OTC medication.If only a- small percentage of self-treatment was shifted to medical practitioners, the patient load would disrupt the U.S. health care system.2(emphasis added). Total retail sales of OTCs in 1982 were $6.2 billion.Thin amounts to about $26.43 per capita annually or $.07 per day.This compares to 1982 per capita annual expenditures of $32.78 for candy and pm, $44.49 for cosmetics and toiletries, $68.38 for prescription drugs, $94.69 for tobacco and $123.44 for alcohol.3

II. The OTC Review The federal Food and Drug Administration _currently is reviewing the safety, effectiveness, and latkling of virtually all OTC drugs in the OTC Review;That Review represents the most thorough, eXtensive, and exhaustive scientific scruthy of OTC drugs ever undertaken by a government agency at any level anywhere in the world. Itis a mammoth project olving a large number of OTC manufacturers and many thousands of OTC undertaken at a cost of many millions of dollars to the federal governniel substantial additional millions to the OTC me. is industry.

Seventet n were appointed to review the safety, effectiveness, and labeling JTC The Panels were.composed of persons in the fields medicine and pharmacology voting it embers_ end _two i..m-voting liaison members represtriting consumers a, .i.dustry;The Panels were 'charged with theresponsibility of recommending to FDA the conditions under ,'itch OTC drugs falling within their ;-view are generally recognized as safe and effective and not misbranded.'Mose 'i'anels compile and issue reports of up to a thamnd pages in length, which contait, their recommendations and which are ptiblished for public comments in an Advance Notice of Proposed Rillemaking (ANPR); 370

After evaluating the comments, FDA issues a formal proposal, whit't,,i forth the agency's proposed action with respect to the various ingredients labeling claims discussed in it.The proposal is subject to further comment, objections, and perhaps an oral hearing.Later FDA issues a Final Monograph; which sets forth FDA's _position on the various ingredients and claims.There are expected to be as many Eiseventy Final Monographs when_ the Review isfinished, one each for the various therapeuxi^_ categories involved (antacids; internal analgesics; etc.);By any measure the CTC Review is a thorough scientific program; and one to which_ FDA has devoted many thousands -of man hours and many millions of dollars.During this regulatoly review, the Assomation_urges that any information or concerns about specific ingredients be directed to the FDA. The OTC Review is the appropriate scientific forum for determination of the safety and effectiveness of ingredients, doses, formulations, and labeling of OTC medicines. To help assure that FDA decisions are base.1 on the best available scientific evidence, the OTC medicine industry has suMitted many of the 20,000 volumes of scientific data.In addition, The Proprietary Association and the industry have made presentations to several of the panels.By_coo_perating with the OTC Review, the industry_ has demonstrated conside-:able interest in assuring that OTCs be safe, effective, and properly labeled for use by the consuMer.

111. The OTC Review of Weight Control Products One instance in which The Proprietary Association submitted data to FDA in connection with the Review involved weigl.t control products, many of which contain phenypropanolamine, an ingredient disceY:ed at some length during the Subcommittee's July 21, 1983 hearing.The FDA's Advisory Review Panel on OTC Nliseellaneous Internal Drug Products had found phenylpropanolamine to be both safe and effective in OTC weight control products.OnJuly 26, 1982, the Association submitted- comments Acopy enclosed)_agreeing With_ that_ coaclusion and providing new data confirming its safety and effectiveness.On August 27, 1982 the Association submitted reply comments (copy enclosed) referencing still more data affirm;rig the safety and/or effectivehem of phenyIpropanolaniine and responding to the comments of these who had raised questions about it. These two submissions of the Association constituted the roost comprehensivecollection of clinical data available vn phenylpropancilaniine, consisting of more than 60 controlled clinical studies involving more than 3,700 patients, all demonstrating the safety and/or effeetivenes)f phenylpropanolamine.These data, together with almost 50 years of safe use of phenylpropanolamine in this country, clearly outweigh the handful of anecdotal reports of adverse effect:.

IV. OTCs and the Elderly A A981 survey by _Louis Harris end Associates for the National C_ounwl OM the Aging, Inc. found that 47 peramt of the public 18-64 years of age believes ti at poor health is a very_ serious problem for most people over 65.However, only 21 percent of older Americans cited poor Wth as 3 very serious personal problem.Harris coacluoed that "A zap between the myth and reality of aging continues to exist . .. This is particularly true with regard to health care.4 371

The elderly have about the ,ame problems_in life as younger people.Despite the public view of a bed-ridden, house-bound older Americans the evident self- perception of a _majority of the elderly is one of relative health and mobility; Researchers Linn and Linn concluded "... age;- by itself, is _a poor indicator of health among the elderly . ...5Aging, indeed, is often a highly personal affairi a 75-year-old man may be physiologically younger than a 55-year-old male.b

Elderly individuals appear to use nonprescription medicines much the same as do younger individuals either as a response to the appearance of symptoms or signs of illness or injury, or as a means of monitoring health or preventing tit;e occurrence of symptoms.Available evidence shows that the elderly population's use of OTCs is directly and appropriately related to their symptoms.? The number _of different OTCs taken_ hy the elderly does not appear to differ from the number used by the adult population as a whole.Roth seniors and the general population use OTCs at approximately the wile rate.5A series nf studies indicates that the average number of these medicines taken by older people ranges from 1.5 to /0 in periods of -two days to two weeks, rising to perhaps 3.5 in the course of ayear.9,10,11,12The average number of OTCs used by the elderly does not differ perceptibly from that reported for the total population, i.e., 1.5 in two days to 2.0 to 2.2 in two weelcs.l3Knapp and Knapp offered the following:"It is often assumed that (OTC) use is high, since older people suffer more afflictions than younger persons.However, two previous studies do not confirm this;_ they indicate that a smaller proportion of thn eld3rly reported using nonprescribed products than do younger people,Since reasonably valid data indicate that prescribed drug use is three times as high in persons over 65 as in those under 65, perhaps the elderly treat their lamer number of afflictions with more potent prescribed drug products ... ."I4

IV.Conclusion

Aging is -a phenomenon unique to each individuaLThe elderlys' health demands are fashioned by specific conditions.As a result, the elderly tend to use OTCs in approximately the same fashion and in the same quantity as the general population.FDA is currently reviewing the safety, effectiveness, and labeling of all OTCs in the OTC Review.This is the most complete scientific scrutiny of OTC drugs ever conducted.Scientific evidence about specific ingredients should be submitted to the FDA for their deliberation in a scientific forum. Sincer'iy,

PRIBTARY ASSOCIATION

1, Senior Vice President, Geller.,Counsel and Secretary

DO'K/b1 8/17/93

375 372

Enclosures: PA Comments on FDA OTC Drug Review Advance Notice of Proposed Rulemaking on Weight Control Products (July 26, 1982) PA Reply Comments on FDA OTC Drug Review Advance Notkeof Proposed Rulemaking on Weight Control Products (August 27, 1082) 373

REFERENCES

Statement _of Arthur Hull Hayes; .1r;, Commissioner of Foods and Drugs, to The Proprietary Association, May II; 1901; U.S. Department of Commerce,-11.S. Industrial Outlook (Washington: U.S. Gtvernment Printing Office, 1978), p. 131.

35th Annual Report on Consumer Spending, July 4,19,13. 4 Louis Harris and Associates, Inc., "Aging in the Eighties:Amreica in Transition," a survey conducted for the National Counsel of the Aging, Inc., Nov. 1981. Bernard S. Linn and Margaret W. Linn, "Objective and Self-Assessed Health in thP Old and Very Old," Social-Beienee-and-Medleine 14-A (1980):311. 6 University of Kansas School of Pltarm_acy, "Effe_cl of Aging on Drug Action, V," continuing education by correspondence (1978). 7 R.V.H. Jones, "Self-Medication in a Small Community," Journal-of-the Royal-CoHege-of-General-Praet4tioners 26 (1976):410-13. 8 U.S. Department of Commerce, p. 131. 9 A,E. Courtney et aL, "Investigation of Use and Reasons 13r Use of Nonprescription Drugs: Report D: National Purchase _report prepared for Ct icdian Department of Health and Welfare (1974), p. 3.5. 10 Robert Kohn and Kerr L. White, eds., Health Care: An Inter:lath:nal Study: Report of the World Health Organization/International -Collaborative .tudy of Medical Care Utilization (London: Oxford University Press, 1976), p. 213.

11 Karen Arm Adamson and Dorothy L. Smith, "Nonprescription Drup and the Elderly Patient," Canadian-Phar-mney-Journal 3 (1978):80-85. 12 Rona'd Law and C lin Chen-ter% "Medicines and Elderly Peopile:_A General Practice S:.irvey," British Medial Journal I (1976)565-68. 13 Kohn and White, p. 343. 14 David A. Knapp and be E. Knapp, "The Elderly and 1'lon2rescribed Medications," 3 (1984:89.

DOK/b1 8/17/83

377 374

THE PROPRIETARY ASSOCIATION 1700 pennwlvon.o Ave;:ne N /WoshIngron DC 20006/Phone (202)3937700

July 25, 1982

krthur gull gayes, Jr., -M.D. Commissioner of Food' and Drug's Dockets_Management eraach (H?A-305) Rem" 4-52_ Foou and Drug Aitioistratton 5600 Fishers Lane Rockville, Maryland 21857 Weight__Coatrol Drug_ Products for Over-the-Counter Human Use; Establishment of a Monograohl Advance Notice of Proposed Rulemaking, 47 Fed, BEI. 8456 et seq. Ipeoruary 25, 1982)-0 1Nockletgo, 81R-0112-2-

Dear Sir: The February 26; 1082 Federal Register contained the above proposal:, which consists of_i_Report_and_Prcposed incqraph of the Advisory Panel_on OTC Miscellaneous Incern:,1 Drug Products, convened by the Food and Drug hdministration under its OTC Drug Review, Interested persons_were invited to submit written comments b" 25; 1982. These comments are filed on behalf of The 1ropr hssociationi_a 101-year old_trade associationi members of which are wgaged_tn the manuiecture_s distribution of nonprescription or over-tho-lount medicinal products. Members of the Association are aubject_to the Federal pood4 Drug and Cosmetic Act t21 W.S.C. 301, et En.) and are interested in and affected by this proposal These conwents are not intended to supersede any comments that may be filed by individual members of the Association. 375

Gen! ommemts

1. t Status of Pror.

The . Iciation note- itz ;:oninuing po.;it.Wa that Mono ft3_issued_unier the 1',:C D.; Review are as opposed_to .56te.o7tve, regulatinl. As co_rhi5 point, the Association he-.c.n ncOrporates by reference: (a) its commentsi (4.tted ii°,7,Th_44 19724on the Proposed Pr.cejures fir C3assificactjn of Over-The-Count-et Drugs; and Ibrits comments, datec June 4, 1972,on the P:nposed Antacid Monograph.

2. Exclusivity Policy

The Association also notes its coatLluing position_tnat FDA lacks the statutory authority.t6 prescribe- exclusive lists of terms_from which_ indications foruse for OTCs must be_drawn and to prohibit labeling terminology which is truthful, accurate, not misleading an(' intelligible to the consumer.

The Fair Packaging and Labeling Act (15 U.S.C. 1453(a)) requires that an item bear a statement_of identity; _ Senton 5021e) of the Food, Drug and Cosmetic Actrequires that the label of a_ drug bear the established lame of the drug_and, if there be none, the common or usualname. As applied to nonprescription drugs; these requirementsare codified_in_21_C.1.R. 201.514 which cites-both -ACES as its authority for requiring a "statement of identity"on thv principal display panel. Section 508 of the Act_ authorizes the Secretary to establish officialnames for dri substances.

None of thev, -',atutocy provisions reveal any Cohgressional '.ntent to grant FDA the authorityto legislate the exact wording of OTC labeling; suchas indications for use, and prohibit truthful labeling terms; Indeed, if manufacturers use some of the terms_ being prescribed by_some OTC_Review_Panels, theirlabeling may well_be in violation of Sec. 502(c) of the Food, Drug, and Cosmetic Act, which requires that label informationbe in -such terns as to render it likely tobe read and understood by consume!a under ordinary conditions of purchase and use;

3; Inactive-Inv:Aelli-emt-Liattnq

The Association disagrees with the Panel's recommendation (page 8473; third cOlumn) that inactive ingredientsbe

,a379 376

listed on the label; Pirati_the listing_of !olactive ingredients would be meaningless to all -but handful_of consunern. Seconds it may overstress the importance of such ingredients and obscure_far_more_meaningful informatiOn; such as directions_for use; warnings,and even the active ingredients. Third; it_may_confuse____ consumers. Products which are similar in their purpose And even in the_number and identity ofactive ingredients may ','.fet widely in th, number andidentity of_inactive inaredients. It is perhaps for these reasons that- current law_does not require that inactive ingredients belisted; AS FDA noted in paragraph_75_of_thePinal_Order_ accompanying the Ahtacid Monograph (39 F.R. 19862;19871 (June 4, 1974)1.

Spet-ific Comments

1. The Proprietary Association suppe-r-ts--blie-Ad-Vi-Stry Pan-el-J-S_Classification of phenyipropanolamine recognized_aa safe and_ effective for -appetite-auiap-ree-S-tdh and weight control. The Association's recommendation is based notonly-on the Cllhltal-evidence submitted_to the_Panel_but also on-t-he even more extensive clinicaldata which has become available since the Pane-l-eotialete-d-4-ta Report.

The Associatibh supports the Panel'srecommendations as to both the safety and the effectiveness of- phenyipropanolamine hydrochloride (PPA) for weight Control;

The FDA; in its preamble to -the Panel's monographi_raised specific safety questions with regard to weightcontrol products and requested further information. At the same time the agency stated that it did_nOt_find_it necessary to take action to remove from the_marketproducts_at _ dosage levels which have a marketing history of us6 in OTf7 weight control drug products._ The maximum dailydcSad .. leveld in there- marketed products ar_an_immediate7r.elease dose of up to 37.5 mg and a timed-release dailydose -of up to 75 mg n'enylpropanolamine, with the t(taldaily dose not i:o_e.tceed 75 mg in either case (page3466, second colUmnl. The following_commenta Sc:ck_to answer theagency's safety questions by providing the requested information( much of which relates to products not before t%is_Panel or was not available in time fOr consideration by the Panel.which concluded its work on Marc: 2, 1979. 377

,n its preamble, the agency has raised the following questions:

a;_To what extent may phenylpropanolamine hydrochloride induce hypertension in normotensive patients at the recommended dose levels?

b. To what extent may phenylpropanolamine hydrochloride aggravate pre-existing hypertension at the recommended dose levels?

c. To what extent may phenylpropanolamine hydrochloride. interact with'aspirin and other medications_that.inhibi' prostaglandin synthesis at the recommended dose levels? These questions are addres'.ed below.

a. To what extent may ph e, .enolamine hydrochloride induce hypertension in patients et the recommended dose levels?

(1) The Panel hal-substant i.nical_evidence.that PPA does not induce hypertensro: ia normotensive fat: nt -s

The -data submitted to the Panel on safetywas more than sufficient, by any standard. At least eight _ well-controlled clinical studies were submittedto the Paneli_eact, of_ which substantiated the safety of PPAas an anorexiant. These numerous supportive studies far exceed the usual requirement of two well-controlled clinical studies. _These studies are_further buttressed by safe consumer use for almost half a century.

Exhibit 1 contains brief abstracts of eight ofthe safety and efficacy stu...tes made available to thePane:.

( 2 )Th_O-S-A-fet mmwe referred to in the_prearAble- which: jai a. e_a ter te_ Pane s- report was submitted; should not alter this conclusion.-

Nine repots were cited in the preamblesas having been made available after_the_Panel's report_was submitted: Two_of these rer-confirmed the results of the studies considered by -the Panel that PPA does not induce hypertension in normotensive matients. These two_positive reports are the study b SIvecman; (_Ref; 7) and the studies of 50 mg, imme.,5Aate andoustaiced release dosages by Cuthbert, Greenberg, and Morley ;Ref. S). 378

Of the remaining sevenrepotts_cited_t,n_i_4/_preamble, six included isolated cases ofLndividuaI advese_reactions. TheS4 were the case reports ofHorowitz, et a1. -[the _ portion of Ref. 2 relating to the_one177year-old WrimariN Prewein, Leonello, and Frewin(Ref.33; King IRef. 4h Peterson and Vasquez 'Ref.5); Lee, Seilin4 and vandongen IRef.81; and Deitz_:Ref.91, In none of these cases_was there any possibility ofverification_of the_actual dose of phenylbropanolaMine takensince the dose was reported b the_pattent and not taken undercontrolled conditions,__ In at least two of the_casesoverdoses were Stated to have cef. 2. relating to the 17year-old-woman; been taken 85 Ref; 41. In_five of the seven cases; rTrimoletsi an tg anOreXiant marketed only inAustralia, waa. deed. In only tWb of the seven cases wasthere_any_f,allLw-Up to determine whether the symptomsreported were CeP eated under the same or different circumstances. Six of_the cases were simply anecdotal_in nature. Clearly, any drug, OTC or prescription; has_thecapacity tw cause ileosyncratic reactions in a smallnumber of individual patients. Only two of the Seven adversereports oite.l_in the preaable_were pdrportedly_of controlledolinical_studies, both conducted_ by Rorowitsi et_l.tRefs. 1 and 2). To the first of thedit the agencyattributes °the raost striking new finding° regardingelevation of blood__ pressure [page 84.66, secondcolumn]. However, both of these studies -c.4 ;rappcopriate_tothe agency's safety evaluation of the recommended dose in_theUnited States because the adverse reactionsreported by p_ Hor040tZ_ were the result_of testingthe 85 mg_Austrelian product "TrimolitS." This product was labeled astimedrelease; but it is open to queStiOn whetherit did in frxt_contain a timed-release mechanism. H. I. Silverman.- wnnae study_ was cited in the preamble ,Ref.710 received ;Ind analyzed a small nuMhet of"Trimolets.,_ As- he has_since reported to FDA, SilverMan found thatthe PPA in the prcduct was immediately soluble in_water and was notin a sustained release form; (See Exhibit 2; p. 2.) Silverman's analysis indicates iTrimolets,"_which had 'aeen used in most -of the_instancesofreported adverse pressuri effebtS; deItverel in_abolus_dose approximately two-anjEl=half tin s themaximum_permitted immediate release dose !,37.5 mg). The reported adverse rea-0.1.0.1s therefore were due to overdose. 379

(3) -Piria-1-1440te4s--now-noerwhelming additional_evidence from controlled cl-inicaletadies that PPA does not cause hypertension in normotensive_patients. Additional studies, six published and 41 unpublished, which were not submitted to the Panel or referred to in tae- preamble, support_this conclusion. More than 3200_ patients were included in these studies; which -were not submitted to the Panel because they became available after the Panel completed its work or were conducted on PPA used as a_nas11 decongestant; _Moaeveri_the dosage levels of PPA in the nasal decongestant studies were comparable to the dosige levels of PPA in weight control products. The published 3tudies include the following:

U. S. Barrett, et- el., reporting in CUrtenf Therapeutic Research 30: 54Y:554, November 19811 on a bioavailability study including 18 volunteers, found no adverse effect: on vital signs; blood pressure, or -ECG; after giving 75 -mg suetained action and 25 mg imnediate release dosage forms of PPA.

Silverman, et al., reporting-in Current V:1F.rapeutic neseareh 29: I83 -94, August 1980,MiTali.; significant changes in either blood pressure or pulse vtlues after oral a4ministeation_of_25 mg pbenylpropant?lemine (od), with and without caffeine, in 37 volunteers.

11_;7,.. Noble, writing in Lanceti_June 19, 1,,32, described three large studies condccted in the paV. two years on more than 400 obese patients. (See Exh'.t 3.) Dr. Noble wrote:

*Data were gathered on a twelv-week, double-blind0 placebo control; -3 study of 50 mg PPA three times daily...; -;a double-blind placebo controlled study -of SO mg PPA combined with 200 mg caffeine in controlled-release form.; at.", a single-blind trial es?. 75 mg PPA in controlled - release form.

"All three dosages ceased no significant increase in -blood pressure in more than 400 patients. 2 patients experienced noteworthy rises in blood pressure after treatmen with 75 mg PPA; but these increases were felt not to be drug related; 380

mean pooled systolicand diastolic bic; L.ceidUre in tha 50mgx3PPA/placeoo stqdy are shown in thefigure;

"our r-r2ituIts confirm -that PPAdoes not cause a significantincrease in blood_pressure even when the amountingested (150_mg/daf) is substantially higher thanthe 75 mg Jose. There wasi_on the,contrary, a reduction in blood pressure as thestudies pcolressed."

7.4;_Blacki_witing on 'The control ofallergic_ Manifestations: By_phenylpropanolamine (propadrine) hydrochloride" in Lancet 54: 101.!.102,1937, reported no blood pressure changes or-insomnia in -41 normot?.nsive_patients given 43 mg dosesof phenylprepnnolamine as frequently as everythree hours. -None of five patients Crived 134 mg within two days sheWed great,Lr ;.;-:;;:e_changes than 10 mmHg systolic. hyW:';-ter;slve patient, i (;*crease in 3__54 mg dose was assoc' . ';o1Lh with systolic blood peestut . r I79 to la Amfig, n3 change in diastolic,,;:i.:Atol;

W.C, Boyer, rUperting on".The clinical use of phenylpropanolamine hydredhIeridetpropadrinel_in_the treatmant_of_alIergic conditiene Allergy 9: _ 509-513; 1939; stated that_headministered 48 mg doses of phenyloropandlatind every two hoursfor five days or more with no effects on blood pressure.

C.A. Mitchell, Writingon_sPossible cardiovascular effect of phenylpropandlatine andbelladonna alkaloids'_ in Them. Res. 19:_47-53,_1968, reportedno pressor effect', after_ giving 50 mg_doses_ ofphenylpropanolamine twice daily in 3't normotensiVe Subjects. The as-yet-unpublished studieswhich demonstrate_ that PPA does not induce hypertension innormotensive patients are as follows: /n an eight week, double-blind,randomiZed study conducted by Rudolph Neble;_M.D.,Ph D., in_San Francisco, CA; 60 patients were diVided into two groups. Thirty__ patients were given 75 mg ofphenYlpret'Aftelamine and 200_mg__ _ caffeine, Llmed-release (od), andthirty patient:, were tited.frelease._ There was no giver. 75 tg diethyIpropien, significant difference in weight lossbetween the groups.

384

381

lo significant changes in either blood pressure_or pulse leasurements were indicated during the test periOdS in comparison with the baseline measurements.

Marianne Sebok,_M.0, SLaff Physician at JFK Memorial lospital, Philadelphia, PA, conducted a six-week, double-blind clinical study of 78 patients who were given either a sustain:A releaSe capsUlecontaining 50 mg__ plienylpropanolamine and,multivitamins_or placeb0; The study demonstrated statistically significant weight loss for the active medication group at all measurement intervals,_ No clinically significant deviations -were noled_in blood pressure_(systolic, diastoliC) and pulse and there were no significant side effects.

5:3lley L: AltschuIer, _M.D.,' Medical College of _ Pennsylvaria, conducted a double-blind, 5 -week clinical study of r, patients who were given either four phenylprooanolamine drops (25 mg) or placebo/drops (tid); This study demonstrat,..d statistically significant weight loss at Week 6 for the phenylpropanolamine compared to placebo at the .04 level of confidence. No clinically significant deviations in blood pressure (systolic, diastolic) and pulse_were noted, nor were any significant side effects reported.

Hoebel; Krosnicki_et al;._Department of Psychology, Princeton University, conducted a double-blind, crossover study in which 5 patients took a sustained release 75_mg ohenylpropanolamine dose twice daily or placebocapsules: xperimentaI and placebo groups were reversed after two weeks SO that the patients served as their on control. Eody weighti pulse1 blood pressure and fastiig blood glucose levels were recorded three times_weekIy. There was no significant change Ln either blood inessure or pulse rate luring the 4-week study in which the ore-diabetic patients received twice the dcily recommended dose of phenyIpropanolamine._ The patients' Signs were monitored in 12 separate office visits durLng the period of the clinical 'valuation.

In a btoeguivalence study at the Massachusetts College of Pharmacy and Allied Health Sciences175 mg phenyloropanolamine (ode SR) was,compared to 25 mg (tid. IR) in 18 volunteers. No significant blood pressure effects were reported.

In a study of 125_male and female_patients by_Alvin P. Wengeri_M.D;,_tablets containing 50 mg_PPA (SR), 25 my pyrilamine maleate, and 25 mg pheniramine maleate were

27-436 0 84 - 25 385 382

compared with placebo for effectiveness asa_nasal _ decongestant. Eighty patients, including all the pl3:.uo patients, were double blinded. Blood pressure evaluations were taken at two and four hoursafter dosage. Overall, there was no major change in blood pressure atthe 95% level of confidence_. The major side effect reported was drowsiness, with 55% of the PPA patientsreporting at least some drowsiness and 38% of theplacebo patients. (OTC Volume 040-151) The following information_was provided to theAssociation by a member company. It is our understanding that the__ company is submitting this information to FDAin greater detail; Between 1971 and 1975, blood pressuredeterminations_were recorded in seven studies of healthy adult volunteers to evaluate the bio-availability of PPA from various formulations. Generally; the studies were conducted as crossover trials comparing sustained-release(SR) and immediate-release (IR) formulations administered assingle dJses. A total of 75 volunteers were includedin the studies, and they Were administered 211 test dosesof ?PA. Blood pressure and pulse rate were determinedbefore and on several occasions after administrationof each test dose. The following test doses were administered: 150 mg IR doses were administered to 35volunteers -on a single occasion during threestudies (42,3,4) (12 received 150 mg as a sing12_dose_and 23 received 150 mg in divided doses over 8 hours);

150 mg SR doses were administered to 48volunteers on 50 occasions during four studies (42,3;4,5);

100 mg IR doses were administered to fourvolunteers On a single occasion during one study(44);

75 mg IR doses were administered to-48volunteers on 50 occasions during four studies (41,2;4,5):

75 mg SR doses were administered to_12volunteers on a single occasion during one Study (#1):

5U mg IR doses were_ administered to 12volunteers on a single occasion during one study (#3):

35 mg IR doses were administered to 12volunteers on 24 occasions during one study (#7). 383

_linically significant increases in_bIood pressure were detected only following administration of 150 mg immediate rtlease PIM, and only in five out of the 35 test doses. E'len in the five cases the increases_were transient_and --lcood pressure retcrned_to_baseline levels during the 1,oservation periods without medical intervention.. Tha 6t,:reases also amounted to only 10 to 30 mmHg, with the laximum reading of 100 mmHg diastolic.

t ai investigators subtitted reports on a total of 337 ,c:ir:s and 51 children (age 12 or under) taking sustained ,selease cough/cold capsules containing_50 mg PPA,_4 mg Qh_nrpheniramine maleate (CPU), and 0.25 mg belladonna el,iloiris. Side effects were reported in 24 (7 percent) iii?': patients, including drowsiness Ill_patients), .r.:.^y retention (1 patient), and nausea (1 patient); r: were no reports of elevated olooi pressure. No side ' :'c-t_ were reported among the children treated.

T40 _hndred fifty patients were given_the_saiae 50 mg nroduct; Side effects were reported by 54 of these patients. There were no reports of elevated blood 7-,.e5sure.

")t .:_eandred_fifty-six patients were given the 50 mg p:oduct. Side erfer.".s reported were: dry mouth (11; b:a...the (11; and drowsiness f21. Medication was not iiifcontinued in any of these patients because of side effects. There were no reports oE elevated blood pressure.

Twenty patients were given the_50 mg product. Side_ _ effects included: drowsiness (1);- increased eye itching and congestion (1); *burnt taste in stomach" (1); nosebleed 1.1). medication was not discontinued in any of these patient7. -here were no reports of elevated blood pressure;

In a comparative study of this product and a Product containia- APAP 195_mg4 pyrilamine maleate 25 mg., caffeine 15 mg, ephedrine sulfate 8 -mg, and phenylpropanolamine hy3rochIoride 25 mg, 25 patien:s took the 50 mg PPA product and 22.took the 25 mg ?PA product. Side effects were noted. There were no reports of elevated blood pressure.

One hundred eighty-eight patients Were_given twice daily_sustained release cough/cold capsules_ containing 50 mg PPA, 4 mg CPM, and 0.25 mg belladonna alkaloids. Side effects were observed in 13 of the patients studied. Dryness of month - a reaction to the

387

C.) 384 belladonnas' = was reported by fivepatients. Upset stomach_ occurred_ in a patient betng_treatedfor ulcer Symptoms; Two patients reported"jitter/nese and __ _ 'irritability " and had the_drugdiscontinued; One case of urinary_ _rdtentiOn developed in_an elderlymale (age 72); There were no reports of elevatedblood pressure.

In another study; -111patients_were given the same_50_mg pradu,:ttwice daily; _Dry mouth wasnoted in two of the patienti. No other adverse effects werenoted. twice daily Eighty ti.ot-P.: were given the_same product Side effects noted were: for -a Jf two to six days; (10)z_drymduth (4); Urinary_retention(1); and blood nausea " There were no reports of elevated pressure.. Eighty -Four patients -were given the sameproduct twice daily for one to 14 days. _There was onereport of dry mouth and no reports of elevatedblood pressure. Thirty-six patients_took the sameproduct; No side effeCt8 were reported. Eighty-eight patients were given -the sameproduct twice daily; There were no adverse effectsnoted; Fifteen normal volunteers receivedthlt_same product for a period of six months. Pre-drug data were collected two weeks prior to dosing_and_oneweek prior to_dosing; Dosage Was one capsule twicedaily.__Two volunteers did not complete the study, for- non -medical- reasons. There was no control_group. ReSilltS of this study showed that the product was safe for_long-termuse Side effects noted were: blurring of_vision (1)and abnorMal SCOTi- probably due 1.3 low-grade_hepatitis (1)._Diastolic bldiad pressure averages_remainedunifOrM throughout the study._ Systolic blood_pressure_averages showeda slight- increase (at WeekS 12; 13 and 20)i though_themean systolic pressure was 125.5 mmHg. At Week 29;hmean_blOod_pressare was 120.5/75_mmHg.Pulse rate dropped early in the study; although this decrease did notcoincide with the systolic blood _ptessure change; It was felt -that all of the changes seen could be related tothe_volunteers' activities during different phaaeS of thestudy;

In a threeyeat StUdy evaluating_the same 50 mg product versus placebo, 450 patientsparticipated; Of the patients taking the_medication,_11.5percent developed possible side effects. Of the patients taking placeboi 385

8,2 percent experienced Possible adverse effects. Thete were, however, no reports of elevated blood pressure. A double-blind study of 178 patients with symptoms of acute coryza was undertaken comparing the effects of a product containing phenylpropanolamine HC1 73 mg and chlorpheniramine maleate 8 mg, in a sustained-release_ capsule; a sustained release product containing PPA 50 tg; CPM 4 mg, and belladonna alkaloids 0.25 mgt and placebo.

Adverse reactions_ were reported by 10 percent of the _ patients taking the 75 mg PPA prods ; 12 percent taking the 50 mg PPA product, and 9 percent taking placebo. There were no reports of elevated blood pressure.

L.S. Cabin reported that mean blood pressure and pulse rates were not affected by 50 mg SR PPA (bid), 0.2 mg belladonna alkaloids (bid), a combination of the above, or placebo in 20 normal volunteers.

Dr. Richard Mulberger found no reports of elevated blood pressure during a crossover study on the- comparison of placebo and a sustained release product_containing PPA 50 nj, CPI 4 mg, and belladonna alkaloids 0.25 mg on intraocular pressure in normal glaucoma patients.

7. Colemoce conducted an open study using I0 volunteers who received 75 mg PPA (bid, SA) for 8 weeks. No- clinically significant blood pressure or pulse effects were seen; (NDA 12-685, OTC Vol; 040012.) 9. Maibach conducted an open study using 15 volunteers Who received 50 mg PPA (bid, SA) for 5 months. No clinically significant changes were seen .in blood_presaure or pulse values. Slight increases %n- systolic bIood_pressure_were seen in Weeks 12, 13, 18 and 19. (:DA 12-685; OTC vol 040012.) An cpen, crossover bioavailability study of 150 mg phenylpropanolamine (od, SA), 75 mg phenylpropanolamine Cod, IR)i and 50 mg phenylpropanolamine (od, /R) was conducted;_using 12 volunteers; No significant blood pressure effects were recorded. (NDA 18-099.)

b. To what extent may PPA aggravate pre-existing hypertension at the recommended dose levels?

389 386

Clinical studies demonstrate that 2PA does not

Two_clinical_studies have come to_this_comclusioni one _ published and one unpublished.-- D.L.-Unger, L. Unger and D.E. Temple reported on the "Effect of an anti-asthmatic compound on blood pressure of hypertensive asthmatic patients" in Ann; Allergy 25:_260-251; 1967; Doses of 25 mg phenylpropanolamine were given three times a day to 21 asthmatic hypertensive patients for one to three weeks. Baseline blood pressure averaged 166/102; within_one hour after_admnistration, the average blood pressure was 164/102; The median -blood pressure pre-dosing was 164/104 and after dosing 16B/102. Five patients had a 10 mmHg elevation la systolic blood_pressure_and five had a decrease of 10_mmHg; -Four patients had e_10 mmHg elevation and fou: a 10 mmHg decrease in diastolic blood pressure. None of the patients studied had to discontinue use_of phenylpropanolamine because of side effects; Tha authors concluded that phenylpropanolamine produced no significant changes in blood pressure at the time of peak blood levels following administration of 25 mg doses.

In a pilot, single-blind, crossover study conducted by M.K. Bradley, M.D., on ten exogenous obese patients with controlled hypertension; oco_clinically significant changes in olood pressure values -were seen_in_patients.who were liven 25 mg PPA (tid), placebo, and 75 mg PPA Cod). (See Exhibit 4.)

c. To what extent may PPA interact with aspirin and other medications that inhibit prostaglandin synthesis at the ret:onmended dose levels?

There is abundant evidence from the long Use of_____ PPA/aspiTin combinations in OTC cough/cold products that such combinations do not induce hypertension This has been confirmed conclusively by clinical studies of aspirin alone- and -of aspirin in com'ainat-ion-wi-ta phenylpcopanolamine;

The agency's request for information on this question arises from a report on a single patient. Leei &

Vandoigen [Ref; 41 reported severe hypertension in a_ _ single patient taking an 85 mg dose of phenylpropanolamine together aith a 25 mg dose of the non-steroidal anti-inflammatory medication; indomethacin, although 387

neither of the drugs was_associated with hypertension in thepatient when given alone. The authors of this sinlle patient report apparently postulated that the decrease in prostaglandin levels due to indomethacin concomitantly reduced the inhibitory action on catecholamine release; As a result, the administration of phenylpropanolamine may have invoked a greater than expected release of catecholamines resulting in profound vasoconstriction and an increase in blood pressure;

The record indicates that hypertension is known to occur from the clinical use of indomethacir4 (A._ Wennmalm,_ _*_Influence of Indomethactn on the Systematic and Pulmonary Vascular Resistance in Man," 0-1-2141-tio-d-.Pter 54: 141-145, 1973;1-9-8-2 Physici-ins Desk Reference). However, no such data is available with regard to aspirin-: Furthermore, the known -long -term concurrent use by patients of aspirin and phenylpropanolamine to alleviate the discomfort of the common cold has not indicated evidence of any significant hypertensive responses;

Th.ire have been several large, well-controlled stadies which have examined the potential for chronically administered aspirin to inftuence blood pressure; No hypertensive effect of aspirin has ever been demonstrated (The Coronary Drug Project Research Group, "Aspirin in Coronary_leart Diseasei"_JChron. Dis. 29: 625-642, 1976; A.A. Copec,_"Efftoacy of Zomepirac_in Oral Surgical Pain," 3r Cli h rmacol. 20: 230=242, 1980).

There are a number of leading non-prescription cold and allergy products which have combined aspirin with phenylpropanolamine in addition to other ingredients (Handboak-of Nonprescription Drugs, Sixth Edition, Amer. pharm. Assoc., Washington, D.C. 1979, pp. 107 -112); _ Many nonprescription and prescription combination products have been used safely for many years in the United States as well as in Europe. If there were any real potential for interaction between aspirin and phenylpropanolamine or any other sympathomimetic, it would-ertainly have been obvious. Yet the market experience has been remarkably free of adverse reactions. A consortium of cough/cold product manufacturers made a presentation to_the cougb/cotd Panel on September 1, 1974; in which they submitted the following data on adverse reactions per 100,090 packages of various leading combination products: 388

Adverse Reactions TOtal Package.; Combination Per 100,000 Sold

PPA_ and 0.282 I_million to acetaminophen 10 Million PPA, chlor- 0.109 10 million to pheniramine, and 50 million aspirin

PPA, chlorphenir- 0;091 l_millionto amine and calcium 10 million cacbaspirin Thtt admirable record of repotted adverse reactions over_ the years_of_use_of these productt indicates how remoteis the poslioilit'y f significant occurrence of theadverse reaction in question; Clinical evidence_that a therapeutic interaction between aspirin and PPA does not occur_it well demonstrated in a 30-iY hUMan study; (Coughi_CoId, Asthmei_Bronohodilator and Allergy Panel Report, Sept; 9; 1976; OTC_VoIume 940299 (1971)). This double7blind, clinidal trial employed a total-patient population of_ 68 (65male; 3 female), and incladed four_identicaL-aopearing_tabletsof different composition provided to subjects by_random__ assignment; Dosage was two tablets taken 4 times daily;

Formula-co,le Odftpdtition per tablet Total Daily Dose

SHP-79 ASA-325 mg 2600 my PPA- 25 mg 20: mg

SHP-79 PPA- 25 mg 200 mg

SHP-80 ASA-325 mg 2600 mg

SHP-82 Placebo

A total Of 25 patients completed 30days_on_the_complete regimen usin_SHP-79 while three other groups of nine patients per group completed the 30-day therapy using the. Other three dosage forms; Subjects not consuming the assigned deitageS were dropped from the study. 389

FC-t-MU-1-Cade SHP-78 SHP-79 SHP-80 SHP-82 __ Subjects Assigned 34 11 11 12

Suhjects Dropped 8 2 2 3

Subjects Completed 25 9 9 9 All subjects wetc provided with clinical and_laboratory evalnations_includinj blood chemistry; urinalysis; blood count, blood pressure; pulse rates, oody weights, and oral temperatures. Pulse and blood pressure were monitored on pays a (day prior-to administration), 7i 15, 22 and 30; One patient_iu the ASA_graup exhibited a dramatiC iadtease in pulse rate on Day 30; This was attribUtei to personal prbbleMs on that day specifically and was not considered to be drug-related. The_ conclusion reached upon completion of tie study was that no evidence of drug-related toxicity was observed or determined.

This study therefore provides_conclusive evidence ofa lack of interaction between PPA and aspirin. Additionally, it provides further support for the proposition that ?PA does not adversely affect blood_ pressiire :lubjects in this study_ingested a total of 200 mg PPA daily for 30 days in individual 50 Mg doses. Tablets were not sustained release. A total of 35 subjects completed the 30-day regimen taking PPA. On the basis of the _dosage employed; ne number of suojCts 2nrolled, and -the length of time they receiveda combination of PPA with the non-steroidal anti-inflamatory Product aspirini no adverse effects relative to blood pressure or oner vital signs were reported.

Summary

The data that was before the Panelk_and_the more extensive data_which_has_become available since the Panel completed itn worki_constitutes_A massive amount of scientific evidence drawn from 60 controlled clinical studies

inVelving more than_3,700_patients. This data _ demonstrates that PPA does not induce hypertension eithet in normotensives or hypertensil,es or When it is in combination with aspirin. This data, together with almost

50 years of safe use of PPA__in_this coantryi clearly _ outweighs the handful of adverse reports referred to in a.lency's Preamble;

393 390

2. The Proprietary Association cecommends_that the FDA accep-tthe-Pane-redeittiendat ion with regard _E77115TIMig for the combinatlatinehydrochloride and caffeine.

The Panel Report recommends Zategory I statusfor the combination of phenylpropanolamine hydrochloride and Caffeine if labeled as an_"Anorectic/Stimulant" [page 8476, first Otiluith). In its preamble FDA invites comment_ on alternate or consolidated label warningsand directions for such combinations, noting_that a discrepancy exists betWeen the directions for use of caffeine in this and another current penpOtal to the agency (page 8469i first column). The warning proposed in the Tentative Final Monograph of the Panel on Over-The-Counter Nighttime Sleep-Aid and Stimulant_Products (Sleephid Panel) was, "For occasional use only;" (5 340;501c)t2); 43 F.R._25602)._ However, the warning proposed by the Miscellaneous Internal_ Panel for Weight Control Products specified daily doses- for -up to three months; (5 357.550(d); page 9484, secondctilUMn).

We do not believe the agency's concern aboutthis discrepancy_is_warranted. Caffeine in combination with pheny/propanolamine_hydrochloridein_weight_control pronItt is intended only as adjunctive therapYi__used_to mitigate the lethargy that may accompany areduced diet regimen. As the Panel Report stated,

". . the Panel had to decide, whetheror_not a significant portion of the dieting population becomes fatigued while dieting. Based upon its professional_experience_the Panel concluded that such a significant patient_population_does_exiat and that the combination of phenylpropanolamine hydrochloride and caffeine meets the three criteria of FDA's combination policy." (Paje 8475, fittt and second columns);

By contrasti caffeine in stimulant products isintended to "help restore mental alertness or Wakefulness during_ fatigue or dtOWSinede whenever these conditions occur. (5 340.3; 43 P.R. 25602). Additt0h; the quantity of caffeine in the weight 391

control products is inherently limited to 600 mg per -day by the current and recommended maximum frequency of dosage of three times a day. AgainI by contrast; when caffeine is used as a stimulant product, the recommended maximum dcsage can be as much as 1200 mg per day (100 to 200 mg not more often than every 3 to 4 hours).

Therefore, it is_appropriate to require_the more restrictive warning on the caffeine products for relief of general fatigue and drowsiness.

Moreover, the amount of caffeine involved in combination With phenylpropanolamine hydrochloride in the weight control products i3 100 to 200 mg. It is essential to note that this is only the equivalent of approximately two cups of coffee; In these dosages; caffeine has been found to be safe, either alone or in combination with other substances_, by three other OTC advisory panel reports, ia addition to the Weight Control Products Panel Report. The most recent of these other panel reports, on OrallyAdministered Menstrual Drug Products, summarized all three panel reports as follows:

"(2) Caffeine. The Panel concludes that caffeine ts generally recognized as -a safe and effective diuretic for OTC -use in the doses noted below in relieving water accumulation symptoms of the premenstrual and menstrual perod.

"(i) Safety. The toxicity of caffeine has been reviewed extensively by the Advisory Review Panel on OTC Sedative, Tranquilizer, and Sleep Aid Drag Products in a report published in the FEDERAL REGISTER of December 8;_1975 (40 FR 57292). That Panel discussed, in addition, the mutagenic effects of caffeine in detail. It found caffeine to be safe ". . when used in the recommended__ oral dose of 100 to 200 milligrams-(mg) not more often than every 3 to 4 hours." FDA concurred with the Panel in the tentative final monograph published in the FEDERAL REGISTER of June 13; 1978 (43 FR 25544);

"The Internal Analgesic Panel also reviewed caffeine_for_its analgesic properties_in_the__ FEDERAL REGISTER of July 8; 1977 (42 FR 35346) and expressed its agreement with the conclusions of the Advisory Review Panel on OTC Sedative;

Tranquilizers and Sleep Aid_Drug Products - regarding the safety of caffeine. This ?arts].

395 392

agrees with the above reportsand concludes that caffeine is safe_as anOTC.diUretiCfor relieving Water accumulation symptoms -of -thepremenstrual and menstrual period indoses of_100 to 200 tg every three to four hours." Second Informat-ton- OTC_Orally Adminiat-e-re-d-A4-6StrualDrug -dtS Report; September 22,1991, 00; 55-56. in In its final meeting onOctober 15-17; 1981, the Panels its teVieq of theMenstrual_Drug_Productt Report, added to this contlutiOn its approvalof a combination of caffeine with a menstrual oroduct.Moreover, it did so based on the same rationale it used forits apprdVal of the combination of phenylpropanolamine andcaffeine in weight control productt, that it,relief of fatigue. The minutes of the Panel meeting state: "The Panel was made awarethatcaffeine is contained_inan OTC menstrual drug_product(a combination_product) which contains aclaim for the relief of fatigue_in_the_preMenttrUal period. Because the Panel has alreadyrecognized that fatigue is a component of thepremenstrual syndrome and_because caffeine hasalready been classified as a Category_I stimulantby another panel, this Panel concludes thatcaffeine is an effective menstrual drUg productingredient for the claim of relieving fatigueOddUrring_in_the premenstrual period." Summary Mi-nut-es-rit the Forty-SOct-h-Meeting of the OTC_Miscellaneous internal Drug Produtts-PAnel, October15 -17, 1981, p. 5.

Finally, it is noteworthy that evenin FDA!s_current inquiry regarding the_use_of caffeineas an added food ingredient, the agencyhas_specificullyeXeMpted_from tnat inquiry the presence of caffeinein coffee and the use of caffeine in drugt.

TheAs'iociat-i-d-isalt-0-e8 with the Panel!sconclusion that vitamins_andminerals shouldnot be constituents of weillit-tOntrol drug products.

The Panel report notes_that someweight control products now on the market contain anumber of vitamins and 393

Minerals in addition to their weight - control active ingredients. The Panel also states its belief that it is the responsibility of the consumer to determine the dietary_regimen_to follow in.order to maintain a well-balanced, low - caloric diet" (page 8472; third column);

W share the Panel's belief in this regard. However, we strongly_disagree with the Panel's conclusion- which is purportedly based upon this belief. The Panel somehow leaps from its belief about a well-balanced diet to the conclusion that "therefore, the addition of vitamins and minerals in combination with the weight control_active ingredients) serves no useful purpose for those following a well-balanced diet" and "vitamins and minerals should not be constituents of weight control drug products" (id.).

The Panel's conclusion does not follow logically from its premise and also conflicts with one of the Panel's other

recommendations, which FDA strongly_endorses in the _ preamble, that "a reduction in total daily caloric intake below the energy output" must accompany weight control drug products in order to achieve significant weight loss (page 8468,_third coIumn;_page_8469, first column; page 8172, second and third columns). Again, we agree with this recommendation.

However, a_consumer who_ follows this label direction and reduces caloric intake below the energy output may, no matter how well-balanced the resultant diet, also raduce the amount of vitamins and minerals previously needed to maintain_the_consumer's bodyweight and frame; The recommended dietary intake of essential nutrients, particularly vitamins and minerals, may be difficult to achieve during caloric reduction, since in_many foods vitamins and minerals are present only in low concentrations. Under these circumstances it may be desirable to provide the consumer with the option of obtaining a vitamin and mineral_ supplement in combination with phenylpropanolamine hydrochloride appetite suppressant in order to replace those vitamins and minerals lost as a result of lowering food intake.

Finally, vitamins and minerals whiCh are dietary supplements are foods and should be treated as such in this_combination. Combinations of cosmetics and drugs are permitted so long as each complies with applicable_ regulations. The same rule should be applied to the combination of vitamins and minerals with weight control active ingredients; The Bureau of Drugs should_impose_no more stringent requirements on such a vitamin and mineral

397 394 supplement than does the Bureau of Foods.

It is in the best interest of good medicine and of the consumer to make generally available the greatest possible variety of safe and effective medication; _Manufacturers should therefore not be prohibited, contrary to the _ Panel's recommendation, from offering such a rational combination of PPA and vitamins and minerals.

4; The Proprietary Association recommends that the_FoA r net's recommendations with regard to Category zhP al. The Ats'iciatIon recommends that the following claims recommended by the Panel to be placed in Category II should instead be placed in Category I. We believe that some_of these claims represent the same claims which the Panel recommended be placed in_Category I but are stated in language that is more readily understood by the consumer. Others are truthful statements or, at moat, amount to acceptable puffery. Indeed; the Panel itself stated that it "is aware that there_may be other_terms that would be acceptable in expressing the same Category I indications" (page 8473, first; column).

These thirteen statements should not_be classified in _ Category II because they do not, in fact, lead to use of the product other than in the manner recommended by the Panel as generally recognized as safe and effective. Each of these Category tI claims is discussed below: a; "Contains one of the most powerful diet ails available without prescription" (page_8476i second column). This is a true statement. The Panel recommended only_two _ substances - - phenylpropanolamine hydrochloride and benzocatne - - for Category I as safe and effective. b. "Contains one of the strongest diet aidsavailable without prescription" iii.). Like claim "a", this is a true statement for products containing phenylpropanolamine. c. "Encourages water loss with a gentle diuretic" (id.); This is a true statement for products containing caffeine; Caffeine has been recommended for Category I as a diuretic by the panel reviewing orallyadministered menstrual drug products and in Category I as_a mild_ stimulant by both the Nighttime Sleep-Aid and Stimulant Products Panel and the panel reviewing menstrual drug 395

products. A fuller discussion appears above on pp..17-19 in_section_2 relating to the labeling_for caffeine/phenylpropanoIamine combinations;

d, "Easy-to-follow reducing plan built around food you love to eat; You will_eat well_but less and lose weight without going-hungry" (id.). Clinical studies submitted to the Panel demonstrate weight loss where caloric intake has been reduced in accordance with diet plans recowended along with these products; _These diet plans- contain a wide variety of nutritious foods, limited only in quantities, not in the breadth of the array of foods specified._ This labeling should certainly_be allowed on products which are packaged with a diet plan; e. "k unique way to help your overweight patient eat leas" (id.); This is a true statement because these products involve the consumer's using a specific; approved medication to reduce appetite, rather than requiring the conaumer to sinply try to follow exhortations to reduce calories without the assistance of medication; g. "Now enjoy _a slim, trim figure. Lose pounds. Reduce inches" (page $475, third column).These claims ere lay descriptions of goal-oriented products -and are helpful in encouraging proper compliance with product instructions. h; "Lose _weight starting today_; Look your_besti feel your best" (id.).This is a true statement; When caloric intake is reduced below energy requirements, the body begins to uae up stored fat for energy. The claim does not refer to--any specific amount of weight loss on_the first day. While the amount may be relatively small, it is nonetheless a start and, once the process starts, the end result is closer than before. Like claim "g4" these claims are lay descriptions of those goals and are helpful in assuring proper compliance with product instructions. i. "The delightful aid to appetite control' (id.). Except for 'delightful" -this is the same as "An aid in_the control of appetite," recommended for category I_oy the Panel (page 6475, first column, -9 2(6)). The addition of "delightful" is harmless puffery,_ fully justified by the fact that the recommended diet plans enclosed with the products contain a broad array of foods. The reasoning for this is the same as for claim "d" above. j:- "Delightfully delicious;_ scientifically formulated to help you control your appetite quickly,loIeasantly" (page 647'5, second column). As in the cane of claim "i", a'oove, 397

COUCLUSION

The Association suppur:_s the Panel's classification of phenylpropanolamine hydrochloride as generally recognized safe and effective_when used_in OTC weight control products; The extensive data discussed above demonstrate t!le safety of phenylpropanolamine at the 150 mg daily dosage level and amply support_the safety of the currently- marketed weight_control_products at the 75 mg daiIy_b,sage level. The Association also su,?pf-rts the Panel's recommendation the.. the combination of phenylpropanolamine and caffeine is -safe and effective if labeled as an "anorectic /stimulant:"

The Associationbelieves that weight control active ingredients in combination with vitamin and mineral lupplements should be allowed, contrary to the Panel's recommendation. In addition the Association_urges that FDA reject some_of the Panel's recomendations with regard to Category II labeling.

The Association appreciates the_opportunity to submit these comments and hOpes that the agency finds them helPfUl.

Sincerely,

THE PROPRIETkRY ASSOCIkTION

James D. Cope ?resident

400 27-436 0 - 84 - 26 398

EXHIBIT 1

'Comparison of the_Anorectic Activity of __ Prolamir.e _And Placebo WithoutConcomitant_Nutritionally Balanced Diet."_ MarianneSebok,_M.D.4_Staff_Physician, JFK Memorial Hospital, Philadelphia,PA. _A double -blind six week clinical evaluation wasconducted with 72 patients who received either 35 mg_phenylpropanolamine and 140 mg caffeine_(sustained release) or aplacebo_twice a day: Throughout the studyi no_clinicallysignificant variations at sitting hlood pressure_or_Pulse_ were observed or reported. PPA patients lost statistically significant amounts of weight compared Withplacebo patients. 'Double-Blind Evaluation of Phenylpropanolamine-Caffeine Product as an Adjunctin the Treatment of Obesity." E. R._Jollyi_M.D.i_BioMetrics Laboratory; cliftor, NJ. Findingt: A double -blind 12 -week study of 63 patients revealed that 21patienta on phenylpropanolamine - caffeine showed an averageweight loss of 15_pounds, and 13 patients onplacebo showed a weight Ioss_of B pounds_over the 127week test period; or1.2 pounds pet week for the phenylpropanolaminepatients compared_to .66 pounds per week for_the_placebopatients. Side_effects_were minimal and equally dividedamoung______pIacebo_and active drug groups. One patient On the active tediCatiOn reported hyperstimulation andsleeplessness and one patient on the placebo notedextreme nervousness._ No significant changes in blood pressure or pulse ratewere observed. 'Double-Blind Clinical Evaluation -of the Anorectic Activity of PhenylpropanolamineAlone Compared tO Phenylpropanolemine Plus_Caffeine inthe Treatment of Outpatients with Exogenous Obesity;' _AnthonyConte,M.D., Pittsburghi PA. In_an 8-week double-blind randomized clinical testi phenylpropanolamine 50 mg wasootpared_to_ phenylptopanoIamirr,_50 mg with caffeine 200 mg(sustained release.) __Of_the sixty -two obese-adults who entered the clinical evaluationE both groups lOst similar amountsof weight. No deviations from baseline were reportedin sitting blOdd pressure (systolic/diastolic) orpulse. 399

Iri_an open:, crossover comparative study, the bioavailability of 25 mg_phenyIpropanoIamine (q4h;_IR)i 75 mg (od, IR) and 75 mg Cod, SA) was tested in 18 volunteers bv Donal:1 Flaster, M.D. No significant blood pressure effects were reported;

Griboffi et al., reporting in Current Therapeutic Research 17: 535-417_1775i found no significant changes in blood pressure or pulse measurements in a double-blind parallel stUdy on 66 volunteers receiving 25 mg PP A_ with 100_mg_caffeineAtidl_or_placebo,__PPA patients_lost significant amounts of weight compared with placebo patients.

- - . _AltschuIer, Sebok_and Conte conducted 6-8 week double-blind, parallel studies using 50 mg ? ?A (od, SR), 3'.5 mg ??A. SR), and 25 mg ?PA (tid,_IR)_i respectively; No significant effects on blood pressure or pulse rate ware reported or observed. Significant weight is was reported.

in a double-blind, crossover study conducted by Bartley G. Hoebeli Ph.D., et al., at Princeton Universityi Princ.Aton,. NJ; phenylpropanolamine (25 mg; tid) reduced body weight in 70 adults significantly more than a placebo pill. During the first two weeks both the subdects ta%ing

the placebo and. those taking_phenylpropanolamine lost_ _ weight, but during the second two weeks only those taking the drug continued to lose. On daily questionnaires those taking thedrug_reported no_change in the way they felt or the time it took to fall asleep.

F.B. Bohensky, M.D., Brooklyn; New York, conducted a single-blind, four-week, crossover clinical evaluation of 60 patients in Dr. Bohensky's private offices; Appedrine (25 mg phenylpropanolamine plus 100 mg caffeine plus multivitamins, tid) was compared to dextro-amphetamine and placebo as an appetitie suppressant. _The results indicated that the phenylpropanolamine group (Appedrine) on the average lost 1.98 pounds per week, the dextro-amphetamine group on the average lost -2.3 pounds per weeki and the placebo group on the average lost .62 pounds per week. No significant changes in blood pressure or mood changes were reported or observed.

402 400

Exhibit 2

Mass_achusettl College of Pharmacy and Allied Health Sciences

September 25, 1981

Ri&erd-Crout, MD, Director Bureau of Drugs,_I-FO.,1_ Food ADrug Administration 5600 Fishers Lane Roceville, MD 20857

Dear Dr. Grout: This letter is In follow-up to our discussions on sustained action dosage forms and your interest In the physiological response to a 75 mg bolus dose of phenylpropenoismine-HCI. You willrecil4 l'rniure, our meeting on Stptemberlith_lrithe Commissioner's Office at which time we reviewed the F.RpublicatIon status of the Advisory Review Panel on OTC Miscellaneous Internal Drug_Products - Proposed Monograph for OTC weight control chug products. A5 an avid student of the _sustained action dosage_form_artd iihenyOrapanolsurtirteil xves_certain, is _I advised you at the meeting, that_ my files Included descriptions of experimental work where a 75 mg bolus of PPA had been admlnIst:red to human volunteers In a piain immediate release dosage form and the hemodynamIc response studied. The SBA for NDA 18499, "Dontsc" provides information describing a three way nzoss-over study employing twelve normal human volunteers. The three dosage regimens were: (A)Two "Contac" sustained action capsules containing 75 mg PPA and 8 mg CPM per capsule.

(B) 75 mg PPA and 8 mg CPM, plain drug as a bolus dose.

(C) 50 mg PPA and 5.33 mg CPP.04 plain drug at 0, 4 and 8 hOurs. 'me bibevailability st_u_dy determined plasma levels at the 1, 2, 3, 10 12 and 24 hour periods following drug Ingestion. In addition, blood pressure and pulse (supine and standing) were taken

17.9 Lontwoos1Avc_nue Boston. Massachusetts 02115 Phone (6171732.2800

403 401

beftio. and et I, 5 and 11 hour; after drug dosing.No clinically significant cheinge In_bitod pressure or pulse in any volunteer during the study wax reported.I /nicht Atdd_this information_is especially Important in view of the report by Horowitz, at al !'llypertinsivo Responses InducedbyPherylpropanolamine In Anorecticend Decongestant Preparations" Lancet, 1980; 10.61.The Horowitz study would suggest one might expect an Increase-In supinediastolic bleed pressures in some volunteers It:letting * 75mg PPA Inasmuch as the dose of PPA in the Australian study1...eas reported to be 85 mg, only SO mg greater.However, ex, clinically significant shangee_mtleod pressure are reported in the carefully controlledstudy suhmltted In support of !VOA 18.099.

At the time of our own studies. (Lack of Side_Effectsfrom Orally Administered Phenylpropanolamine and PhenylpropAnolamine with Caffeine: A Controlled -Three -Phase V;udy", CurrentTherapeutic Research 7., 18.1494;_I988)_ we received irnall rrimber of the Australtan_product "TrImolets"Jor eviluatior. "Trimolets" was the 85 mg PPA prod .1 reported on in the Horowitzpaper. the cspsules contain.! a -fine yellow powder labelled to contain_DiSherlyre- partolamine 85 mg plus tc,rrous gluconate, calcium_gentothenatee thiemimilbotliiin, pyridoxine and nicotInamide. Only threecapsules were received essaying out at82.2 mg, 79.7 mg and 83.5 mg respectively (awe! lige 81.8 mg).The PPA F these capsules was Immediately soluble in water, and not in a sustainedrelease form. Regarding the Integrity of the sustained releasedoug: form marketed Iri_nis country, I would like to add thatour laboratories have, for years ThswrevalustedhutvIreds of pelletized sustainedrelease PPA dosage forms marketed by the Thompson Medical mpany. Our .-lasorstories provide a periodic quality control _Meltend_assurance .fanttion for Thompson as a. further. .check .to insurecorniallisndo-of manufactured _dotage_ forma with produc. specifications.I am pleased to Indicate we have never encountered a productwhere "dose. dumping" under In vitro tasting occurred and the sustained- release character of a dosage form .wes compromised. The number.of Safety end welity_controlltaps tiken, prior to batch release,assure safety and efficacy of the sustained-Action product and provides an ._ exceptional degree of quality_ assurance ruling _out any possibility of the occurrence of "dose-dumping." bloavallidoUltystudio -.have provided assurance of- the effectiveness ofthe timetkeleate activity with excellent correlation between a single dose of the timed- release formulation (75 mg _and three &set of the immediaterelease .dosage term (25 mg) takes? at 4 hour_httervaG. F6nce, ongoing in vitro quality control, In our experience, assures product performanceon level consistent with the in vivo results.

404 402

Thompson's 7!m_g timed-release PPA dosage forms are menu. factured to confor n with the following In vitro dissolution pattern limits. , Hour 96-Re tease ...., Rela. . e I 30 - 45 22.5 = 33.75 .- . 4 "'so- 75 .37.5 - 56.25

80 - 100 .60 - 75 . . The dissolution pattern Is developed by sampling at 1, 2, k 6 and 8 hours.

Itrust these comments are a helpful sequel to our earlier discussion and provide some assistance to you.

Sincerely,

PFEIFFER PHARMACEUTrAL SCIENCES LABORATOR

Sprairman, D.Sc. Professor and Executive Director

F-115/if cc:Mrs. Barbara Bayer Mario.1 FInkek MD William E. Gilbertson, Pharrn.D. Judith K. Jones, Ph.D. mi. Mark, Noviteh, MD Dr. Edward Steinberg 403

THE tANICET. JUNE 19. 1982 1419

of imam involvement and with ptesentation either in childhood or CEFTAZIDIME AND SALMCNELLA in-adulthoo treatment would generally iin conjunction-with Card and_catlenota_(hrair 22, p. 1152) llama ocher s_pecalists. Seeing patients together in combined clinics Salmonella warm septiaemia treated with aftuidime I g three would seem to be the best way of-achieving this. umesaily tea MuseThe minimum inhibitory comentratio n Tor air_ofdefiratairstelated_to_many_kthildr_iiiiriallY that strain wu 0.25 piing. Probably the dosage sal too low. We handicapping genetic disorders. Clinical geneticists Must not have treated a 33-year-old African non, who had skate-cell anaemia encourage this being_sataed to Umit their involvement to and an osteomyelitis -with 1_ op_Anwstisro IMIC_023 elitxdr, diagnosis and genetic counselling. successfully with, at first, 2-g twice daily-for 17 days and, after an 'LAMM/W.14M Cibilaosis Novecal. operstinta_l_gariMaily_Re_Rays. The_Enne rnatroutiample Maath.er 1,421 :PG Kam taken during operation was sterile A higher dosage it probably eautied &MammTi(and, possibly, Sktella) infections. Of interest would be information on nompultility_ a the Witted plIENYLPROPANOLAAOINE AND BLOOD PRESSURE organisms to other-currently available antibiotics and successful phenylpropsnoVinine(PIA) has been safely-wed ireatment_of the infecnoto by CeTra-zieltne, where prior antibiotic in the U.S.A. for over forrzyears ea a nasal decongestan; your April therapy had failed. 10 editorial raised the passibility that PPA in weight control Laboosay. preparations could Produryinuated_hlOotratuus. feasaoltotrpoitfasedos --In the past two years, I have done three large studies incur obesity Ho/waist-Cln Froldisear4laa 70. inSan_Erandisco aria ATeetinfsee_dcsage farms of PM. Mai Gomm WOLEGANG Snout More than 400 obese patients were studied. The results will be published elsewhere. Damwerepthered on a twelve.wee.14doubloblin4 MYOCARDIAL CARNMNE DEFICIENCY IN ACUTE placebo- controlled study of 50 mg PPA three time daily MYOMRDCAL INFARCTION (nvice_the_tecomrnencted _dose for weigliticia);_adaublebfimd Sat,Dr Sunski and coUcagues am.% p.114)-reporteddecreued placebo controlled study of 50 mg PM weaned with 200 mg lather fres Larnitintin thetnycanfniniefehanithais &lire ne in coati oiled release &an; and a single-blind trial of 75 tog patients and a concomitant rise in ocylcarnidne. These donate are PPA m controlled. release form. reratedus a remerO_of wxurnuhtafree Any sad(FFA)and kelp All three dosages caused no significant increase-in :food pressure chain acyl.CoA esters secondary to chronic hyposis which in turn Us more Man 400 Patients. ilatientsciperienced rissewatthy_rises inhibit, adenine mscleotide wanslacase.' This metabolic device, in blood pressure after treatment with 75 mg PPA, but these oho observed in do/ heats during the reversible nhoe of increases_werefelt not be ilnIg_rebted iscLiemia'- seems to-act IS a IMMS mechanism tending to relieve The mean pooled systolic and diastolic blend pressure in the SO myacrdll _liiury-Suad'etiLidUatedtttei croriniatisition_of mg. 3 PPA/placcho study-are-shown in the figure. aogenous 4carnitine during acute and chronic cardiac iechaemis. Our results confirm that PPA does notating significatitincreue Usage expertmentalischeenua, however, progressively more-MCA pressure even when the amount ingested (ISO mg/day) is Laminae is lost the lonAn the ischaemia huts.' The two findings aubstsitiallylfigber r6aiidle_recommended7Stng dose. There was, strongly suggest that the maintenance of physiologicd lads of on the contrary, a reduction in blood pressure as the studies Lkannine_ind ati_itylearnidni taf eecarititine_ratin ply an progressed. important role in the control of the metabolism of the injured Eailmilid NM eases Quit- myeardium. Sao 'mono Gahm. m U ta. Runous E. Now We measured" heart Laminae lath at necrojwy in awn patientewho had had acute myocardial infarctions and in four who haddiedfnen cansenotberibmihartiMene.IndsefiraMmipihe r tissue unales woe removed frcenthe nemodcarea, front the border sononallrmo myocardium; wbereasis corral Lcansitine lcrels were asap* determined in spesimenstaken from the left ventricular welh.-The necrotic myocardial areas had ktwo_Lionsinste_levela_whil_the l arder _Ism amo_showed intermediate values between necrotic and healthy surrounding no_efaczenitTsry_bittiriniffaimyeardlil L-carnitins values in the controls and those found in the besIth_y surrounding tissue of those who had Wed frosts myocardial infannice. We did not observe -short and long chain carnitine ems in the nuistionnenoefeitherarma, ptentsablVisittausetstsFecilzmns removed 24 h alter death 2U the L-carnitine content is_present in the km unmet -Corm, result hydrolysisduring the perW since death end during stone at -25C for 10-15 days. Thad-0min ourexperimental model free Lansitine corresponds-to total &rititTneTrutinonmentiasuppoitaby ftiet_aitheauue Learnitine levels we Bawd in the healthy toyocanfurn were identical to the -total Learnitine levels mewed by Cederbla in the myocardium of hart surgery patients , I. Sbooisi,Vmarti,Martli-disID,-liabaX Aq1CatiMiloso radios* tnaMossmso adasMososolioss.A./ThasstIMGMIIII GM 2. 7/Coso&PIsis. kora loelmtennastamod orsMoboisdosiss omoribot sod oo. An* &dew IheMpAM at 70.m. Dt-IMMEL-Ctoo/FA_Oseoma oodasseptomitimEic Dogmata P NU.A. 4.1.1.6..7...... 17sc Val IV. Wm Yak: Asama hos,:771: hE 4 Seamen IMIlioddit, lindiclitHabatiMals fP.CaosidIDJ. Goismisdoodisa J.kamosukalsame-0.12._Le111;12,11 t CsilestsbdAtiodassaklimMaloCarimmoso Weems. iv boom owls Mesa systolic and diastolic blood prMUYV. mom CM Cleo Am 1074 Mi HI. 404

...xmioit 4

MIOMPSON_ MEDICAL COMPANY, INC, 919 THIRD AVENUE NEW YORK. N.Y. 10022(212) 6513-4420

PROGRESS REPORT ON THE PILOT STUDY

"DOUBLE-BLIND SAFETY AND EFFICACY EVALUATION OFPHENYLPROPANOLAMINE HCI

IN EXOGENOUS OBESE PATIENTS WITH CONTROLLEDHYPERTENSION"

Chiefrervest-itater:

Matthew H. Bradley, M.D. 1160 Kane Course Miami, FL 33134

Submitted to:

7nompson Medical Company, Inc.

July 16, 1982

Prepared-by:

K.M. Farragher

7 405

CONTENTS

I; STUDY PURPOSE

II. PATIENT POPULATION

III. PATIENT EXCLUSION CRITERIA

IV. STUDY 7ESIGN

V. STATISTICAL METHODS

VI. STUDY RESULTS

A. Patient Population Profile

B. vital Signs Data (Safety and Analysis)

1. Blood Pressure and Pulse Data

a. Baseline vs Biweekly Treatment Values b. Baseline vs Biweekly II, 1, 2, and 4 Hour Values c. Intraweekly Treatment Value Comp-:isons

2. Laboratory Elood Analysis Data

a. Biweekly Treatment Value Comparisons b. Biweekly Laboratory Values

3. Laboratory Oral Temperature Data

C. Weight Loss Data (Efficacy Analysis)

D. Side Effects

VII. CM.CLUSIONS 406

I. STUDY PURPOSE

The purpose of this study it tO__evaluate the efficaCY,_tolerance,and Safety of phenylprapandlandhe HCI (PPA)_vs placebo_in the treatmentof exogenous obesity in patients with controlled,stable hvoertens4.,e diseases.

II. PATIENT POPULATION PROFILE (12) patients in the age The patiier peganIatieti profile included_twelve range of 25 to 67 yea'rs with exogenous obesity andcontrolled, ecable hypertensive disease;

A Controlled, stable hypertensive disease_was defined asdiastolic blood_ - pressure at_Or below;941mHg_ The_hypertensive disease state wascontrolled With thiatide, with and without concomitant potassium supplements.

EXOgetions obesity_eas_defined as at least 10%, but not morethan 55% overweight aL ca1.21ared using, the revised Metropolitant Life insure-fide Cetpany Statistical Book 47:1, 1966.

ITT: PATIENT EXCLUSION CRITERIA medication which_would_interfere 1. patients curr,nclvusing concommitant with the evaluation of safety and/or efficacy, i.e. MAOinhibitors:

mydeardiaI infarction 2. Patients who have suffered i recent (3-6 months) or with severe cardiac decompensation.

3. Patients who have had recent (3-6 months) surgery.

4. patients with elevated venous blood pressure.

5. Patients with unstable or accelerated angina' episodes.

6. Patients who exhibit complications of hypertenstion or arteriosclerotic cardiovascular disease, such as cerebral ischetia or uremia.

7. Patients who cannon adhere to the protocol visit schedule.

8. Patients who are pregnant or lactating.

9. Patients who have been on- weight tedUction program:_or medication during the three Weekt prior to this study's initiation.

IV. STUDY DESIGN

The studyas a single blind orossover_study which extendedfor six weeks according to the fel-161:1-4 Medication and dosageschedule: mK e.t.d. "7" PhenyI:rooanolamine_25 ma. caffeine 100 (one hour before meals) WEEK 2

4O 407

IV. STUDY DESIGN (Continued) WEEK 3 G Placebo; b.i.d. (10 a.m. E. WEEK 4 4 p.m.) ;washout period WEEK 5 _4_ PhenylprepahOIaMtne 75 mg. o.d. (10 a.m.) WEEK 6

Data was collected according to the following schedule:

INITIAL VISIT (Day 0)---- Chest XRay, Background 6 Clinical Data

!macui VISITS Body Weight, Vital Signs_loral_temperaT ture; hlood preatiire, pulse), Appetite Suppression (degree; duratiLl); Side Effects

BIWEEKLY _VISITS.: ,. Physical Examination, Supine Electro cardiograph_Trating;BIood Pressure and Pulse 4, 2 a 4 hours after initial dose. V. STATISTICAL METHODS

Adelytit Of_Variance (ttests) was performedon the differences_ between__.. baSeIine values and (a) biweekly treacment_group values Add (b) biWeikIy treatment group values taken at 4, 1, 2, and 4 hours forblood *testate ind pulse measurements.

ThiSe vatiabIii Were also tested for significantdifferences for each treat ment group_dUring each treatment week (i.e., weeks 1 vs 2; week 3 vs 4; week 5 vs 6).

Laboratory VaIdit (glucose, triglycerides, cholesterol;GGTP; SCOT; LOU ; s_dium, potassium, chloride and oral temperatures)_werecompared for sled fieient differeneti_bitween baseline and end of treatment_group values; _ Also; labotttot'; Values for placeboVSmedicated treatments were competed;

Hunger feelings_(appitite suppression) and weightloss measurements were axmmined for differtnees between baseline andend of treatment group values; A 95: Confidence level was used to test the statistical sienificance ofthe data. VI. SriDY RESULTS

A. PATIENT POPULATION PROFILE

Ten of the_initlal twelve patients completed the study. Patient 04 and010comPleted_the fitat crossover leg butwere discontinued because of protocol violations (Uaing_in MAOinhibitor and previous time commitments, respectively); Neither Patient reportedany adverse reactions.

Table gl presents the patient popuutioh profilein terms of age, sex and weight/height characteristics;

,410 408

TABIS PATIENT POPULATION PROFILE

PATIENTS ENTERED PA-TIENTS-G-E6IFLEM)

IsTM8ER /2 10

SEX Male_ 3 2 Female 9 8

ACE (YRS) Mean 144 Range 25-67 25-67 -- ______-__------_--_ BODY FRAME Small 0 0 Medium 7 7 Large 5 3 ------___-__-______--___----__------_-----__------% OVERWEIGHT Mean 26.65 -23 :8% Range 12-54 12-54

INITIAL WEIGHT 178.8 Mean_ 184.7 Range 149-284 149-284

IDEAL WEIGHT Mean 139.9 137.2 Range 125-184 125-184 ---_---____----__-_---__------

B. VITAL SIGNS DATA

I. Blood Pressure and Pulse Data

a. Basoline-vs Biweekly Treatment Values

Table 2 lists the mean and range values for olood pressure and pulse valuem at baseline and at end of eacn treatment period; Figure I displays these values graphically.

No statistically significant differences were found between baseline values and end of treatment values for blood pressure or pulse measurements.

4 11 409

IBLE 2: RAN4ENALLES__OF_BLOCD_PRESSEKE_ImmEgL6 PULSE KATE_DATA (Feats minute-) . _ AT THE END CF EACH TREATMENT PERIOD (Mean Values Witkin Parenchesit) N.I0

WEEK -2 WEEK 4 WEEK 6 '1EA SUR EMMT BASELINE (25mg PPA) (Placebo) (75 mg. PPA) 100 mg caffeine Standing Pulse 54-88 (73.0) 64-96 (76.4) 56-88 (75.8) 60-98 (80.0)

Supine Pulse 54-92 (73.3) 56-88 (72.5) 56-84 (73.6) 64-96 (76.2)

Standing Diastolic 74-92 (84-.2) 70-94 (82.0) 70-90 (82.2) 64-92 (80.2)

Supine Diastolic 70-94 (83.4) 60-90 (80.0) 62-90 (81.2) 60-90 (79:6)

Siacding Systolic 116-142(130.6) 100-166(125.2) 114-148 (127.8) 100 - 158(134.2)

Su?ine Systolic 114-170(133;3)108-164 (127.8) 112-150 (132.4) 90- 150(129.6)

Figure 1. MEAN BLODD PRESSURE (mmHg) AND PULSE RATE (beats/minute) VALUES AT BASELINE AND END OF TREATMENT WEEKS.

170

160

ISO

140 130 ...... 123.

110

100 90-.

GO /-80 ...... 53170 I 407660 204-60 44 20440 two, wat..es 104 30

0 2 4 6 TOM N10 410

VI. STL'OY REsurs

1. Blood Pressure and Pulse Race Data f:oncinued)

b; Baseline vs 6. I. 2. 8.1 4 How. Valves

Table 3_liscs the means and -the range of values_forblood pressure and pulse measurements at baseline and_at and 4 hours following the first hiediCatiOn_dosage_for_all three treatment groups. Figures 2 throUgh 4 display the means of these valuesgraphically.

significant differences were found between the mean No 2 and 4 hours blood pressure and pulse values ac bateline_;_and_1/2,_1. following the -first medication_dosage;_alchough elevenstatistically signlflcaat_diff`crences were_seen. Clinical insignificance is easily determined by examining (a) the small changes between baSilinevalues and (b) the small differences between-"texcheOk"VilUes_for_normocensive patients (diastolic bloodpressure,- 60 -90.i mHg:_systolicblood pressure. :0C-140 mmHg: pulse. 70-90 inolg) and treatment values.

4 AIM 1.251C. .5 4 PanUTE(4.44.19 fffff ) DATA or y, I, 2owl 1101:63 IALCIS or StZD 972 M.10- (mos yalmos 5111141p 00000 torls) _ 4 801651UTLI I .10U1_4/1711 110,214 Arlta O-NBUW-474111 ,701CaTlee Inartist -I5N9::660_4"ye

1-.-111.ACM 40m16(79,11 6-96 OS, 11-100 54.81 7140002.9 5.4.,,, P0,16 4-64 174.0) 1:440..61 44.18)1141 51.4314:41 1.-91 152.5) 5,1, 1.4;,56 41::: (VrO 4.1041).8) 51... :1%1 11:461(L:C 74.94 .57.01 56.98(71,0) I n;:lOo Z e-90 Ina,.- 50., MA 78.4_I. 6-10 1-63T ^-57 711.41 31:1-I+51CLIC (45.04 92.4851110.41. .oo 4155.7 64.144 MO al 50.151 3.0 511056(13.61 108-Ion47[6..1 .7 1.-1.-1.14,21.1(, 1 1 450451(1 t1,,,,,:t 110.1.t1.6 rrA ..a. II .61 mminnzwimEUMMEIMOIE:11IMMIECIMPlan= 53-100 MI. 4_, i1i:1lit2.71 IC 'I--31 ME=EISEREHEMMIIINCEIMMERIVEILIM_7040 163:0 MarriljtErIECOMINICEIMMIIIMIF 11i ! 4 ;J.C-410, (....-1 It. mmii,imq.-w[iIIICIEIESFEEIHIESIMMIIIIMITEEIKUnglallIMIEciazie-DINEN .26-160 113 1.8.160

51641 :(icmot V fffff (p00.)5) 411

Figure 2. MEAN BLOOD PRESSURE (mmHg) -AND -PULSE RATE (beats/mInute) VALUES FOLLOWING TREATMENT ONE (25mg PPA,100mg eat reine,lid).

170 160

150 140% !rm. C. 1 130T ...... 170 A

90 Ousiske ftorl Powno 60T 70+ 90 ...... 60.9. so ...... 50- 70 40 1r 60 So,. I...on 30 50 We &Moo. 20 40 10 30

30 60 120 240 TIME (wow...) N10

414 412

Ficure 3. MEAN BLOOD PRESSURE (rtiftHg) AND PULSE RATE &eats/minute)VALUES FOLLOWING TREATMENT TWO (placebo).

170 160 +

150 140- 130 4.4 Stow 4641.;.me.

120 444 ...... 0 110 + 0 100+

90 80 70+90 .... 60 + 80 ...... 50 70

10 60 StawhAi 30 50 20 40

0 30, 60 120 240 . 0 'Mg irnwri1112) N.10

Figure 4. MEAN BLOOD. PRESSURE (mmHg) AND PULSE RATE (beats/minute) VALUES FOLLOWING TREATMENT THREE (75mg PPA, OD)

17041. 160

150

140 fry. MOMonsmos 130 ...... 120

110

100 90 4...... -4.444 80 70 90 ...... ,. _...... ,...... + 60 .d. SO ...... + SO f 70 40 T 60 avow menu.* 30 4 SO Ilu.N 20 1 40 My 30 .1mr.ameno 0 +:444444444itsco4.144:o4=4,roaC 240 0 30 60 120 MAE rman.4441 N10 413

SILTY RESULTS

1. Blood Pressure and Pulse Data (continued)

e. Intraweekly Treatment Comparisons

No significant differences were found between any blood pressure or pulse measurements within treatment weeks in all three treatment groups, as shown in Table 5.

IIIICLI: ILA%11.000 1,4151111 14.0 A.nut 4 ...... mino41 144511.1112 /555 11711.47%/41,1111 1,8111 M.1JCS 0.10)

981471107 1 7118.41,1.57 7 TR LAM= 1 113_, PP4. 100 41 1417717e. 11:04.0..1 173 so PP*. 34) - 2.1.4.1- 111ra_ 1 ylo.1 tan 7 3[/1 1 VW( A 3111. 5 5171 1

:(1tanding) 115,1 II:.0 15.: 12.2 11.1 10.2

JlastnIL (73147m1 81,1 90.0 10.1 11.2 U.: 11.2

77.(114 15(An3I00) 137.4 175.7 178.0 176.1 177.7 1...7

ivtot le (543:01 112.8 2:7.1 114.0 113.4 115.8 131.1

i 31. (5148.40 71.1 71 4 76.6 MB 78.5 80.0

131. 15,1441 71.1 77.5 71.0 73.1 ILI 76.7

Laboratory Blood Analysis-Data

a. Baseline vs Biweekly Treatment Values

No significant differences were found between any laboratory variables for all study treatments. These results are presented in Table 6.

r1s,1,...7 v.w.es (11.10) ?AO[b. .LAN1AICAA1017 VAWLI roil usatyk 417 1138:11Y .*

1.41..47027 LRIVAL 1751:r.44,10C1-% TALAV.L. 7 T118.4:718. 1 T!ST 14141 14121.147 Call... 4(411 Placea..1 (15, PIA 4.1-/j_ Glucose (88/41/ 254110 104.7 103.0 106.7 1071.7

7947 ...c4,1.14es (.8/411 744147 :98.5 177.1 114.5 172.0

Chc14.t.r11 124/311 151-100 741.3 :21,1 756.5 765.0

Cr.T? NW 7.11 47.2 20.1 17.0 70.0

0007 1.411 10-33 72. 6 27.4 76.5 71 01

3.311 14/11 17.0-725 171, 123.1 121.1 149.1

1ee3 .= '1440.11 1154141 112.1 160.4 141.3 140.1

rauscut 1440/0 1.5.5.0 6.7 ..1 1.7 4.1

CNI ttttt (4414) 45-110 101.1 107.1 101-3 107.7

416 27-436 0 84 - 27 414

VE STUDY RESULTS

2. Lainnaaory-81-Ged-Mirl-vsts-Diria

a. Baseline vs Biweekly Treatment Values (continued):

Table 7 lists the patients with laboratory values outside the normal range. Laboratory values which increase continually or sporadically are listed in the bottom half of the table.

TAM 71re IMS MI LANNIATORT MI MS Ott Of 1114 ICIVIAL 11.4102 0-10)

tl!,:t" uCleee et.rter.etIll" !COT J. 344144 feteeollatCh lortie

I 1[4) 111 3 111

1 ---TIIV ,_ '--4--."--T711.-11T= .40Tat a .01....w KUI -- AIILIIT 135641111,tW, 42444 1= 4 14.631,1C 1117 33.3,312 144321343 1C:ttr)1.41,41171.....32aal

Chico.. 143/41) 3 105 130 IV 47 5 _35 ra 130 95 9 1U 106 T76 la

1041yeethtse-- 3 301 110 153 141- 14041) 7 /Tr 1ST ru HT NI M it 'TT Ts .-. ca.1,..01 7 eel 397 401 won) il n3 Trr 'Sr ITT

LEM (6/1) II In 303 142. WI COTloft)) 13 45 it 72

() Values Derseee4 etIntteased etersolteellte fts 4sselime 441ges. ) Vsles 3.4,....4 42_16424064_06tIng611 -000b...1 lo. .01.... II Mater eLratee eatalde_the-ner461-reecs. Vele.. owswe the 6etatal 44444 all unittella.1 ottet Vla. WreTt the ettraal 44444 rt. toehrl Ind Wiest 1664)4.=.14.mo64...44.4r) 415

STIM RESULTS

2. Laboratory Blood Analysis Data (continued):

b. Biweekly Laboratory

With the exception of one instance. statistical ccmrarisons of lab values between treatment one, two and three showed no-significant differences. The- exception occurred between treatment one (25mg PPA, 1004 caffeine, tid) treatment three (75mg PPA,_ed) glucose levels At week_4_ the m,,n glucose value was 108.0medl and at week 6 the mean gluc'ose value had decreased to 99.4mg/d1 (p(.05), a change of 8.6mg/d1.

3. Oral Temperature Values

Oral temperature values did not fluctuate. All temperature values were 98.6.

C. WEIGHT LOSS DATA (Efficacy Anlysie)

Patients receiving phenylpropanolamine lost more than 1 pound per treatment seek as shown in Table 8.

TOLE 3 'ICAOcur:LArtYtOLICHT LOSSNLEK(11")

TREAT.LOT VETCHrLOSS 25e1 PPA (Lid) t.1 73.1 PPA (ad) -1.4 Placebo -0.63

TheSe_valuss_exceed the FDA finding_of_a mean_veight_lass_of l_pouod__ per week among 10,000 patients receiving prescription weight loss aids.

Ninety-three percent (932) of the patients reported that they expert- enced_none or slight hunger feelings-after receiving -25mg PPA (tid), or PPA (od). _Seventy-one percent (71%) -of the_patients reported that_they experienced moderate or marked hurger feelings after receiving treatment 2 (placebo). n: SIDE EFFECTS

One patient (47) reported feeling nausea and dirtiness during the first week of medication (25mg PPA, t.i.d.). 416

VII. CONCLUSIONS

The lack of Llii,a117 significant differences between baseline and 11. 1, 2 and 4 hour blood pressure and pulse values provides safety data for the use_of phenylpropanolamine appetite ,.ppressant products by-stable, eon - trolled hypertensive patient_popuistions. In addition, differences between baseline and end of treatment values showed non-significant differences for all comparisons plus intraweekly treatment comparisons showed no siltni- ficant differences. These results justify the continuation of this pilot study.

The effectiveness of phenyIpropanolamine appetite suppressant_aids_for stable. hypertensive populations was also substantiated in_this_Oilot__ study. The patients receiving 25mg (tid)* and 75 mg (od) showed a mean weight loss of 1.9 pounds and 1.4 pounds per week. respectively, which exceeds the FDA finding of a mean weight loss of 1.0 pounds per week for 10,000 patients recei,Ang prescription weight_loss aids, as presentid in the "Review of Amphetamine-Like Drugs by the FBD"__Ili Obesity_in Perspective (Vol II, Part II. Brayi GAS ed.Washington., DC_, Government PrintinvOffise;_ 1976. pp.441-443). The incidence of reduced hunger feeling (86%) was greater among patients receiving active medication.

"plus 100mg caffeine. 417

1700 Pennsvls/oniii Avenue N 41/4/0thingion. D C 20000/Phone 1207) J4J 1700

AugLat 27; 1982

ArthUr HU1I Hayes, Jr.,_M,D,_ Commissioner of Food and_Drugs Dockets Management Branch (HFA-305) Room 4-62 Food and Drug Administratibh 5600 Fishers Lane Rockvilleo Maryland 20857 Reply Comments: Weight Contr61 DrugProducts for Over-the-Counter Human Use;EstabliShMent of a Monograph;_Advance_Noticeof PropoSed RUldniakingi_47_Fed. 322 8466 et seq. (February 26, 1982), Docket No. 81N0022

Dear Sir: Comments_were due on July 26, 1982, on-the above_proposalo which consists or a_Report and ProposedMonograph of the__ Advisory Panel on-OTC- Miscellaneous InternalDrug Products,____ convened by the Food_and_Drug_Administrationunder its OTC Drug by hUgust 27, 1982; Revie'.i. Reply comments were to be submitted -The Proprietary The reply comments are filed on behalf -of Association, a 141-year-old_trade_association,_theactive members of which are engaged-inthe manufacture and distribution of nonprescription -or- over -the - counter medicinal subject to the products,Members of the Association_are Federal FoodL Drug and CosmeticAft (2I_U.S.C. 301, et-sel.) and are interested in and affectedby thid proposal;

Theta tepIy_comments_are_not_intended tosupertede_any which may tie filed by individualmembers of the Association.

Comments Which Atteri thatPhenyIpropanolamine Causes High Blood Pressure or Other AdVerSe Reactions.

The principal concerns of theCenter for_Science in the Public Interest (CSPI) regardingthe safety Of

REDDESDONG MANUFACIUDERS OF NONPRESC11117110N NEDIC145 418 phenylpropanoiamine_rest on what CSPI describes as the known tendency of PPA_to raise blood pressure....' (CSPI, p. 5.) To the contrary, there have been_no_studies submitted or citedby any participant -in this proceeding that support theproposition that PPA has 'known tendency' to_raise blood pressure at the dosage levels recommended in the AMPS;

In its discussion of the relationship between-PPA and hypertension, CSPI states that after the Panel's report on- weight control products containing PPA was submitted to FDA in 1979 'several reports -of- alarming cardiovascular reactions to recommended- quantities of_PPA_appeared in the the medical literature.' (CSPI; p. 'In_response_to this - evidence,' CSPI goes on to state, -'FDA took regulatory action_to_remove_ from the market all weight control products_containing single, immediate-release doses of greater than 37.5 -mg -of PPA_and timed-release doses of greater than 75 mg.' (CSPI; -p: 6.) This is incorrect. In actuality the action by FDA to limit products to single, immediate-release doses of not greater than 37.5 mg of PPA and timedrelease doses of not greater than 75 mg was based on the agency's position that products which contained higher doses were not- marketed -OTC prior to December 5, 1975, and were, therefore, new drugs.' (47 Fed. ma. 8469; February 26; 1982.) CSPI cites the double-blind trial reported by_Horowitz; at al., in 1980 as substantiation for its assertion that the available evidence does not support a Category I classification for any dose of PPA.The Association commented extensively on the Horowitz study (see p. 5 of PA Comments), and now wishes to aid that the study_by C._Ai_Mitchell* referred to on page 7 of our comments; did not_report comparable results with the 50 mg timed-release portion of the_study.__In_a_cross-over study, six normotensive volunteers received placebo or -50 mg PPA plus 0.25 mg belladonna alkaloids. Blood- pressure_and -pulse were recorded every 15 minutes for the first 90 minutes and_every 30 minutes for the next 90 minutes after dosing. Mitchell reported no statistically significant differences between drug and placebo on mean arterial pressure or pulse.

Nor did 11 percent of_those_persons who received 50 mg of PPA in_a timed- release -form in_the Horowitz_study develop 'significant, sometimes severe_diastolim.hypertension,' as CSPI asserts. (CSPI, p. 6.) Horowitz reported that four of the 37 subjects had a diastolic reading of 100 or more, and reported_ that one of those four participants had a maximum supine -blood pressure of 145/110 mm Rg.Presumably the subject with the 145/110 mm Hg. reading had the highest diastolic reading of the four_subjects_with_readings of 100 or more.This is not equivalent, however, to reporting that the subjects had 'severe 419

diattOlic hypertensioni' as CSPI_statest nor did_Horowitz so classify those subjects:- Moreover, although_ Horowitzstated that three subjects -in the 85 mg-portion of_the_studyreceived anti-hypertension therapy, he did not report that any of the subjects fn the 50 mg portion of the study received anti-hypertension therapy. CSPI further asserts that one_would expect the elevated diaStelic_bIood pressure readings reported_in the_subjects in the HdroWit2 study who received a 50 mg timed-release capsule to occur in more people if a 75 mg -dose were ingested._(CSPI, p. 7.1In fact, the Noble study cited on page 7 of our comments demonstrates that no such result occurred. The_speculations_of CSPI are further negated by the fact that in 1981 approrImately_five billion doses_o_f__PPA_were taken in the ferth of- cough /cold and weight control_OTC_productst with only a handful Of reports of adverse reactions; which appear to be either idiosyncratic or due to overdoses;

The comments of the California Association of NeurOlogiCaI Surgeons; Inc. and those of Arthur P. Shinn, Pharm. D.; BeeChhe Laboratories, raise a_similar safety concern when PPA is ingested;__However; the reports cited_in those comments simply dd not indicate that there is_a relationship between_PPA_and__ the reactions repOrted_when_PPA is ingested_at_the lose levels recommended in the ANPR. The comments_of the California_ Association of Neurological Surgeons, for example; report_tbree cases of adverse reactions after ingestion of -PPA; _Case_I_and Case 2 aret respectively, a report of an overdose of anOTC _ weight7control productt and a report of ingestion of an illegal. 'look- alike' product. Case 3 is a report of an averse reaction after the ingestion of_an OTC_"diet_pill,' which is not otherwise identified; As_to_Cmse_3t it should also be noted that the report states that vomiting_occurred immediately after ingestion and that the adverse_reaction_occurred_after the vomiting. It is unlikely, therefdret_that_the adverse reaction resulted from the ingestion of the 'diet pill ;'

Similarlyi_the reports cited by Shinn involved overdddea, ideosyncratic reactions and/or_illegal combinations. Case 1 inVOlVed_h patient with_a history_of epilepsy who_had_a_seizure. apparently coincidentaIIy_with_the ingestion of two combination don-O/c-old products:- In Case 2 the patient had_consumed_three to five ounces Of whiskey just prior to ingesting two 'black capsules,' each containing a combination of -200 mg_caffc.inet 25 mg ephedrine and 50 mg PPA, a comhination Which FDAhas since declared to be an unapproved 'new drug.' (47 -Fed. Eel; 35344; August 13i 1982.1Case 3 again involved two 'Erick capsules' containing the same illegal combination. 420

CSPI asserts that the_recommended_label warning i8 inconspicuous and inadequate to protect_persons who have hypertension, heart diseasei_diabetes_or thyroid disease from ingesting weight control products containing_PPA; (CSPI. PP. 12-13.) As an examination of the label-warnings on these products shows, the warning is clear and conspicuous, as, _ indeed, Section 502(c) of the Act and FDA's regulations require it to be.

CSPI further_ asserts_ that 'Iclonsumers have an understandable tendency to believe_that_drugs_available on an OTC basis are_ safe for most potential purchases,....' (CSPI, pp. 12-13.1 We believe that this -is true -and that it -is aIsty_fully_consistent With the philosophy of making medication- available to the consumer on an over-the-counter basis.-In- stating- that consumers do not read labels because they believe that OTC medicines are unqualifiedly safe for everyone, CSPI is not really questioning the safety of PPA as an OTC; it is really questioning_the_fundamental principle of self-medication itself -7._that _people are_capable of_using an OTC safely and effectively if they follow labeling directions.

Comments Which Assert that Phenylpropanolamine is Unsafe Because of Alleged CNS Effects

CSPI states that PPA is unsafe for use in weight control products because of reports of adverse CNS effects resulting fromKthe ingestion_of_PPA.___CSPI concedes that "(Ilion of these incidents proves_definitively_that_PPA_can_cause mental derangement,' but contends_that 'the structural_similarity_is there...' between- PPA -and the amphetamines, adrenaline, -and related sympathomimetie-amines. (CSPI, P.3.) CSPI couples the structural similarity with case reports in the United States and other countries linking PPA with adverse CNS effects._ CSPI cites several reports, including the Dietz survey listed in the preamble to the ANPR as Reference 9, as support for the proposition_that_there_have been 'scattered accounts that even normal doses_of PPA_may_sometimes cause or aggravate psychotic episodes, hanucinationsi_or_other severe_behavioral aberrations- that mimic- amphetamine reactions.' ACM, p.3.) We subtit that the Diets survey does--notsupport the proposition that there-are adverse CNS effects- associated with the use of PPA at the dosage levels of the products currently marketed or the dosage levels proposed by the Panel.- AC CSPI points out, the Dietz survey is composed of scattered accounts. (CSPI, p. 3.) In addition, the seven cases referred to in the Dietz survey, which were taken from record cards of 421

patients in emergency rooms, are accounts of isolated cases of individual adverse reactions. There was no possibility of verification of the_actuaI doses_of PPA_taken since the PPA was not_taken under controlled conditions, and there was no follow-up to determine whether-the symptoms reported were repeated under the same or different circumstances.

The other reports cited by CSPI iCSPI, p.3, fn. 9) also fail to support the proposition for which CSPI cites them. With regard to_the_Achor and Extein_report_of precipitation of- bipolar affective disorder in three patients who_had been taking diet-aid products containing PPA,_one patient had been taking twice the recommended dose, and the dosage for the other two patients was not reported. Therefore,:one of the cases clearly involved an overdose, and the remaining two cases may have as well. Furthermore, according to the report, all three patients had histories of mood disorders;Finally; the report did not describe_the patientss_psychiatric_status_immediateIy_prior to

taking the_diet aids, or after they were withdrawn; It is - therefore- impossible to evaluate-whether PPA played any role in the psychiatric episodes reported.

The Schaffer and Pauli report cited by CSPI involved one patient who ingested three to five pills each day from two separate bottles of diet Pills. Obviously, the reaction of that patient is of no use in any evaluation of PPA.

The report by Norveniusi_et_al; cited by CSPI, dealt with complaints to the Swedish Adverse Drug Reaction Committee. It is unclear from the report whether the total number of complaints was 61 or 65. In any event, five Patients were reported to have had psychotic episode:, but the report does not give dose levels for any of the patients. Since 49 of the patients were under_age_16,_it_is_probabIe_that many -of these patients ingested accidental overdoses: Moreover; the report_ specifica/Iy_notes_that one l7- year -old male_had_taken !large' quantities of a PPA and brompheniramine combination product. In view of the absence of data on the precise dosage ingested in each case, the report essentially has no probative value. The Wharton report relied upon by CSPI describes a psychotic episode in a patient taking a_cold_medication_containing 125 mg of PPAi phenyItoxolamine, phenacetin and thonzylamine; He exhibited paranoid psychosis after an eight-day period in which he had ingested 30_tabIets. _He was treated for-the paranoid- psychosis, but eight weeks after recovery he suffered a similar reaction, although he was not taking the cold medication at the time. Therefore, the psychotic reaction apparently did not result from the ingestion of PPA. 422

Finally, CSPI cites the Kane and Greene report of three- patients who took nasal deconjestants containing PPA. The reaction of two of the three patients simply does not support the Center's position. One of the patients had previously been treated for_undifferentiated_schlzophrenia.That patient's reaction may well have resulted not_from the ingestion of PPA but from a-preexisting mental condition_.___Another patient_had_ used 'two bottles' Of the decongestant within -one week._ There is no indication as to the actual amount of PPA taken at any - one time. Accordingly, once again, the report cannot be cited as support for any proposition concerning PPA. To_summariZe, the five published reports discussed above include 13 patients who experienced psychotic episodes. Three of the_patients were chiitlren_a_years old or younger, who probably ingested accidental overdosesi_and one_patient was _a 17-year-old who reportedly had taken 'large quantities' of a PPA and brompheniramine combination_prodUctAmong the remaining nine patients, one had taken more than the recomendel dose; another may have taken more than the recommended dose 'the only information available was that the patient took 'two bott1eeli One apparently took two PPA-containing preparations, but dosage was not specified; four had histories of affective illness or_schizophrenia and one oE these took more than the recommended - dose: and_one patient_ experienced another psychotic episode- eight -weeks after he_had_discontinued_use_of_products containing PPA. Moreover, it- should be reiterated that ' _ substantially all of the complaints reported_by_Norvenius, et al,, were complaints of restlessness, irritability, etc._ Furthermore, these reports primarily involved children 15 years old and younger and, therefore, most of the cases undoubtedly involved accidental ingestions or overdoses. CSPI also cites another_case in which alleged adverse CNS reactions occurred:-( CSPI -p. 70_ The_case involved a 44-year-old woman who developed 'confusion fandj_grand mal seizures' approximately an hour after taking a 75 mg timed-release weight control capsule.As a careful reading of the report of the incident indicates, the woman-had-preViously experienced grand mal seizure reactions to cough/cold medications. Therefore, her grand mal seizure reaction was idiosyncratic. There is, moreover, no established contraindication for sympathomimetic drugs for epilepsy.

Relying_on Porter s Dietschi_Inc._v._Federal Trade_Commissoni 90 FTC 770 (1977), aff'd, 1979-2 Trade Cases I 62,795A7th_Cir. 1979), CSPI asserts that PPA is unsafe because the advertising for weight control products containing PPA_ShiCh does_not__ include a health warning is misleading. (CSPI, p; 13); The 423

relevancy to this proceeding of the- FTC's- action in -that case_ is dubious at best. In any event, CSPI misstates the scope of the ruling in Porter & Dietsch. The holding was limited to the particular advertisements at issue in that case. It was not applicable to all PPA-containing weight control products. Moreover, as FDA knowsi the Panel recommended a number of label warnings foi these products, as discussed above.

There is an absence ofany evidence establishing that adverse CNS reactions are a side effect of the ingestion of PPA at the dosage levels proposed by the Panel. In fact, the marketing experience of cough /cold and weight control products containing PPA in the United States is support for the proposition that adverse_CNS_reactions_are_not_a_side_effect of the_ingestion_of PPM.; Furthermore; -the marketing experience is_supported by_a recent_doubIe-blind, cross-over study by_Seppal.a, reported in the British Journal of Clinical Pharmacology. A/The Seppala study, which also included antihistamines that provided an active control, reported no euphoric effect and an improvement in perception and reaction accuracy following ingestion_of ppA at a 50 mg dose level. SepPala stated_in_conclusion_that °Mt is_noteworthy_that_mood_elevationi.was not_noted_after jtreatment withj_phenyipropanolamine.'Accordingly, in_view of the results of.the Seppala study the accumulated experience from the testing and marketing of cough/coli and weight control products which fails to indicate that ingestion of PP; in the doses proposed by the Panel results in adverse CNS reactions, and the fact that the cited reports of adverse CNS reactions are either reports of ingestion of doses above the recommended dosage_level or_are_isolated incidentsi_we_submit_that no evidence_has been identified that indicates that_ingestion of PPA at the_recommended doses is unsafe because of possible adverse -CNS reactions. we believe, therefore, that further_ clinical testing is unnecessary in order to evaluate the safety of PPA at the dosage levels under consideration.

CSPI, citing a letter from the British Department of Health and Social Securityi states that only one PPA weight control product_is_marketed_in Britain and_that the product_is_a _ prescription drugi_and implies that_the FDA Should adopt a simiIar_p0Iicy withrespect -to weight control products containing PPA. (CSPI,-p. 13.) It-should be noted that Britain does permit the marketing of OTC drugs containing PPA. Henley and James markets Cantac, its OTC cough-cold product containing PPA, in Britain.

426

; 424

Comments Which Assert that PPA Is Unsafe Because it is a Drug of Abuse

CSPI_and_G.13; StickIeri_M.D.,_cite ding abuse_as_a_reason_for placing -PPAon prescription;_ (SCPI, pp. 3 -5z- Stickler, p.2.1_ CSPI relieson_Natonal Clearinghouse for Poison Control Center reports andStickler, citing no sources, simply asserts that PPA 'is thenumber one street-drug, at least-in Minneapolis -and probably inother cities in this country. (Stickler, p. 2.)

The Association has several comments on the points raised by CSPI and Dr.Stickler with respect to PPA and drug abuse. (I) National Clearinghouse for Poison Control Centers (NCPCC - Date;- (a) Ektrapdletions Of NCPCC data must -be made with__ caution since the data are derived from only 10% of the nation's poison control centers, and the

10% are not necessarily a valid sample. .

(b) The data_reflect all_reports_of ingestions or other incidents;_ whether serious_or_not._ Host_of the reports discussed by CSPI_with_respect_to_PPA were made by telephone, rarely involved hospital - contact and, -on the average, resulted in mild, if any, side effects.

(c) As CSPI concedes (CSPI, p.5), "a large percent of the Clearinghouse PPA cases involved children The Association notes that this percentage is_Iarge_indeed_over 40. _That isA over 40% of the cases involve_children under 5 years of age. Placing-an ingredient_on_prescription_to_ _ eliminate unsupervised ingestions by- children is not, the Association submits, a legal or wise measure. As FDA knows, The Proprietary Association and its members have long been active in working to reduce_ unsupervised_ ingestions of medicines by childrem;._ The_Association_hae_participated in governmentsponsored_conferences and various educational activities on the_subjecti_while its members have been experimenting with testing, improving, and using various -forms of 'special packaging' Since 1955- Needless to sayi the Association supports CSPI's attempt to reduce 425

accidental_ingestions, including- ingestions by children, of_the products subject to this Proposal; The Association believes, however, that attempting to combat such ingestions by placing a drug on prescription on the basis that it is not generally recognized as safe' Eor OTC use is not proper.

Section 201(ptof_the FDC_Act defines a new drug' as_one which is -'not generally recognized ...as safe and effective under the conditions prescribed, recoMmendet, o.su-qq-est-edi-nthe labeling-thereof....' (Emphasis added.1 In so defining the term, Congress recognized that_any drug can be unsafe if used incorrectly, such as_ taken internally_when_it shouId_be used topically and/or_taken in_excessive amounts. Congress therefore sought to address the-question of whether_a drug is safe by considering the safety of the drug in connection with the adequacy of its labeling, incluling its dosage recommendations, method of administration, warnings, and other precautions. _Therefore, unless the_labeling_a_the products subject to the_proposal prescribes, recommends, or suggests ingestion_of amounts which are toxic, such products do not meet the statutory definition of new drug.'

The Consumer Product safety Commission (CPSC)ion the other hand, has tbe_express_CongressionaI mandate 'to protect_children_from serious- personal injury or serious-illness resulting from handlingi_asingi_or ingesting' these and other products by requiring- special packaging where appropriate. 1140 U.S.C. 1472(a)(1).) Accordingly, the Association suggests that CSPI submit to CSPC what information it has on accidental ingestions of such products by children. FDA, howeveri_is_without authority to proceed against such products as new drugs.'

- Nor is placing these products on prescription necessarily a useful means of protecting children from the-dangers of unsupervised ingestion of drugs. Unsupervised ingestion by children is a function of the accessiblity of the drug to children and the adequacy of parental supervision, not of the legal status of the drUg as prescription or OTC.

428 426

of (d) The Clearinghouse data incIude_a_number suicide gestures. The Association notes that_ none_of_the_gestures succeeded. Noreoveti_the Safety of_OTCs,_ which are produCteintended to be taken according_to label directions,Cannot Properly be judged_on_the_basis ofdata regarding their use iU attempted suicides. MOre_detailed_liscusaion of the (e) Pot a general but data contained in the August,I98I_NCPCC Bulletin/ the Association isenclosing as Attachment A_written comment* ofCherIes_Winicki Ph.D. Dr. Winick is _a Professor atthe City___ University of_New York Graduate School,CO-editor of the _Journal_of_Substance-Ote-and-Abuse; contribUting editor of the -J Issues and adAlctiVe_Diseasesi_and_aongtime consultatt to/ and principal investigator -on, -many-projects funded by federal government agenciesconcerned with drug abuse.

(3) Potential for Abuse of -1ThenvItropatolamine CSPI states_that_the_Griffith/ et-al.,study Whidh indicated thet_PPA_Iacks abusepotential is of questionable Significance.___No_basis_for_this criticism is given -The Griffith_ study_was_ well-controlled and conclusively- establishedthat dr40 self-administration procedures with laboratoryanimals have provided_an important_conceptUai_end methodological_focus for the pre - clinicalassessment _ Of abuse potential. _In_this_study,coriddeted At Johns Hdpkins,University, a_quantitative ratio measurewas deVeloPed which permitted_comparison betweenthe reinforcing ptitenCy_of either phenylethylamine anorectics and cocaine in Iabotatory_baboons. _The well-controlled study clearlydellonstrated that PPA has a zero potential for abuse.- Seppala______confirmed this in humans, finding no-mood-elevating component from 50 mg immediately availabledosee.JI

(4) 'Amphetamine Look-AIikes" what the (a) CSPI questions the safety_of_PPA for Cetter bees -es the ingredient's contributionto drug_ablite frOM tho_saIe_of_!amphetamine look-alikes,' described by -CSPI as_combinations of PPAL ephedrine, and Caffeine; (CSPIi_p-3A1 The Association notes that suchcombinations are 427

not Category I_combinations nor_is anyone, to_the Association's knowledge, proposing that they be placed in Category I. They are thus not relevant to discussions of PPA when used according to the terms set forth in the ANPR. Indeed, FDA has recently taken the position that such combinations are unapprovednew drugs.' (47 Fed. Rea. 35344, August 13, 19820

(b) Since 1980,_43 states -have considered and-33-have enacted legislation mhich prohibits trafficking in what CSPI describes as 'amphetamine look-alikes.' Both the U.S. Drug Enforcement Administration and the American Merlical Association have developed_moleI_bills_along_this line, The Association understands that in states which have passed -such legislation, the problems of abuse of _such_'1dok-alikes" has substantially declined. In addition, both FDA and the Post Office Department have instituted seizure actions against a number of manufacturers of such products.

(c) As noted earlieri_Dr;__StickIer asserts that PPA !is_the number one street-drugi_at least in Ninneaponsi_and_probany in other cities in this country;'_ (Stickler, p.2.) It appears that what Dr. Stickler is discussing is not PPA in the recommended dose but rather PPA in the illegal combinations discussed above.

Comments Which Question the Effectiveness of PhenvIcronancIatine

On page 1 of its comments, CSPI states that one of its concerns regarding weight control products containing PPA is the lack of evidence to support claims of efficacy.CSPI attributes this lack of evidence to the drug manufacturers' elIeged_refusal 'to reveal to the scientific community_details of_most of the studies_purported_to back_claims_of efficacy NeedIess_td say, all studies submitted to FDA under its OTC Drug Review on PPA are public;

CSPI also states that the Panel's conclusion that the new studies presented to it (Refs. 6 through 11) established the efficacy of such products was "qualified by the statement that

'each of these studies is defective_in one_or_more_important _ ways'.' (CSPI, p.__15.)__This statement is incorrect; The Panel concluded that PPA is effective and their finding was 428

unanimous: What the Panel in fact stated was that:

While each of these studies is defective in ets covered- , the Panel believes that the combined evidence of these studies_does_establish the effectiveness of phenylpropanolamine hydrochioride.__(47 Fed. 1211;_3475, February 26, I9820(Emphasis added;) CSPI states that the results from the IO double -blind studies in the public docket do not 'support any claim of efficacy. (CSPI, p. 19.) To the contrary, the following data represents the weight loss achieved by patients on phenylpropanolamine and patients on placebo_in eight clinical studies presented to the Panel: Average Weight Loss Per Week

Phenylpropanolamine l ;16 lbs; -Placebo ;56 lbd.

The difference is .40 lbs. Moreover, severai_years ago FDA evaluated 210 double-blind studies in which prescription_appetite suppressant products werecompared against placebo. _These_studies__ represented 105_new drug applicationand contained data on nearly 10,000 patients. Scoville2/,_In reporting on these results, indicated that of the 4,543 patients-0n- active drug and 3,100 patients on placebo, the weight loss averaged 0.56 pounds per week more for each patient on active_drug than on placebo. The results with OTC products containing_PPA_compare favorably with this resuit; The average_weight_loss_achieved by patients on the phenylpropanolamine program was_.60_pounds_more than the weight 1088 achieved by the_patients on the placebo-plus-diet program. It is also important to point out that, when phenylptopanolamine was evaluated in these double-blind clinical studies against either a lactose- capsule or an active prescription medication, each patient was giveni in addition to medication, a -1250 calorie diet, as_weli_as_explicit directions from_a physician. In other wordsi_in_each_case_the_!placebe_was associated with a diet designed to cause_Ioss of weight_under_the direction of_a physician._ Therefore, the amount of_weight_Ioss__ achieved by patients -on the phenylpropanolamine program was even more significant- because the PPA was being compared with another active program, that is, reduced diet and medical directions as well as placebb. 429

In ccncluSion, we submit that thecited_studies are sUffieitht to support the efficacy claim_made_bythe various mamufacturers, as the Panel concluded;

CsPI cites_the_FTC_decision in thePOttet & Dietsch caset______discussed_abovei_as if it_Wett a findingon the ineffectiveness of__PPA_for weight loss; (CSPItp. 14.)_ Again, -this misstates the case. The_gUeStion put at issue by the_compiaintin Potter & Dietsch was not whether the claims_of weight_Iossart NM- but instead whether at the time_theywere -made (Porter-s Dietedh] possessed rehsonable_substantiationfor them.' Porter & Dietsch, Inc ., 1976-1979 CCHFTC COM-Plaints andOrders t 21,320 at 21i329._ The CommissionMali no finding as to the efficacy of PPA as an anortetid; 21031. Port-e-r-&-afetscht supra at

CSPI also asserts that weightcontrol_products containing PPA are of no long term benefit becauseusers may regain weight when use is discontinued. OTC weight control products containing PPA are appetitesupprestantswhich are marketed as an adlunct_to assist_the motivated consumeron a diet. The products_are_marketed_with dietS thatare based on_a_reduction_ in_caloric intake and the lhbelling_states_that_weightcontrol will'oceur_only if the product is reduced; taken_whiie caIoric_intakt is Ntit do these products claim thatweight Will not be regained if the person's caloricintake is increased.

Moreover, there is_evidence which contradictsCSPI's assertion,__Dr._StanIey Shachtett Ptofessorof Psychology at Columbia Universityi redentli, concludeda_long-term study to determine whethtt tiVetweight_patientscontinue to maintilin reduced_ weijht aftet successful_weightloss program;2/ Asked about their weight historiest_of40 people who were obese at-the outset, 25 reported losing_atleast 10 percent of their Weight (an average of 34.7_pounds)and therefore becoming no longer obese_ithat Jet vithin_IOpercent Of the average weight for their height_and age)tand retaining at that weight for average of 11.2 years; an

CSP1_also cites the Statement in theAmerican Medical Association's AMA )rus-avalwatIons PPA are that__OTC_prodects containing only mi- sally effective"ACSPIiPP; 14-15;) This characterization has been_repeatedverbatim year after year, but investigation of the_AMA'ssources reveals that no scientific studies_or proof of -anyStitt are cited by the AMA to support this description of PPA;

432

27-436 0 - 84 - 28 430

COMMente Which Question the Validity_of theSilverman stUdy Cited by the Agency and by ThePropriet-arm-A-sseatation

In its critique of the Silverman_study,-.5_/ _c ed in the Agency's_preamble and in CSPI; -CSPIstaees_that_sthe_ experimental design is flawed in des manyimportant_waya_that one couid_have predictedin advance that no- effects wouId_be_ seen. (CSPI, p.8.1 When analyzed, this criticism- amounts to three_points: that_the_study groups were too small -and indlUded only normal, healthy volunteers;that blood pressure valueS-Vere preSented_as_means_for each subgroup,rather than individn011yi-and_that only one_of_the threesubgroups was double-blinded. _HAVing_consulted_with Dr_._Silverman, the principal investigater_for_the cited study,the Association believes that these criticisms -of thestudy_are_entirely without merit. The sorcalled flAWS= were all t' result_of_a study design explicitly established in accordanci: 'h accepted clinical procedures to eliminate investigator orof bias.

Thus, the pool of_37 voiunteers_who receivedactive medidatiOn- was diVided iAto three smallersubgroups at separate sites With a separate group of qualifiedinvestigators_each_conducting its study independently Of the ether_twosubgroups. he total number of volunteers who received_active_medication was_ _ actually the same as the number ofvolunteers who received actime_medication (in an overdoes-of 85 tag) in-One of the_ Horowitz studies on which CSPI relies soheavily._ In_fact, CSPI eharacterizes_that Horowitz_study as1aitge. (CSPI, p. normal, 6.) SithilarIy, the_fact that_the_volunteerswere healthy edUltS was in accordance_with acceptedpractice and was also true of both of the Horowitz studies. The use of group means to report blo94 pressuresis an acceptable biostatistidel procedure:_/ Pinany,_the_fact that only_one of-the three subgroups_ was double-blinded is also not a 'flaw° in thestudy; Each of the throe subgroups was_treated differently on this scorefor sound reasonsStudy_of one subgroup_was open_in order tosimulate the conditions-in the_actual overrthercounter consumeruse of the product. The study_of a second grouP_was single-blinled and the study of the third subgroupwas_deublerblinded. The fact that all three stibgroups_stuOied underthese various conditions produced no significant blood pressureeffects reinforces the conclusion that at the tested -dosage level, 25 vigi which is the mast commonly-marketedimmediate release dosage level, phenyIpropanolamine produces noadverse blood pressure effects; 431

In_conclusion, it_shouim be- noted that the Silverman study is only one_oE some 60 controlled clinical studies, cited by the Association in its comments, which demonstrate that phenylpropanolamine does not induce hypertension. This mass_of positive data, together with almost 50 years_of safe use of PPA in this countryk clearly_outweighs_the_handfuI of adverse reports referred to in the CSPI and other comments.

The_Association appreciates the opportunity to submit these reply comments.

Sincerely,

THE PROPRIETARY ASSOCIATION

James D. Cope President 432

FOOTNOTES

Seppala, et al., BritishJournal Of Clinical Pharmacology, 12: 179-188,1981: icalPsvchiattV; 13:1383, 1978. 2/ Griffith; et al.; Biolo9 amphetamine-like drugs by Scoville, B.A.; 'Revf.-ew of 3/ Administrations' ,9hes4tV in the_Food and Drill International Center Series On Porsoect-iveT-fowart, Preventive-MedIelne, Vol;ILABrayi_G.A., ed.), U.S. Government Printing °Mee;Washington, D. C., 1975, pp; 441-443. Short, PSvcholonv Todm, 4/ "Don't SeIl_Habit Breakers August, 1982: 28: 185-194, 1980: 5/ Curren tThera0eUtic Research, MacMillan, N.Y., 1958, 5/ Goldstine, A., Biostatistics, p. 272. 433

SOME CCfniENTS ON POISON CONTROL CENTER REPORT ON PHENYLPROPANOLANINE

August 1981

Charles Winick, Ph.D.

' _; 1. The_August_1981_Bulletin_of_the_National_Clearinghouse for Poison Control Centers carried an article onyhenylpropanolamine Weight

. " - Control Products.

For the calendar year 1979_, there were a total of 144,262 reports , of all substances. Of these, 739 were diet aids, of which 328 were named- phenylpropanolemine products, or aboutkof 1Z of the total. I obtained this breakdown from several conversations which I:had with the senior author of the Poison Control Center report. .. 2. As someone who has worked for years in theeAdemiologyla substance abuse, on behalf of the National Institute Of Drug Abusi-ind other agencies, I believe that the tone of the Poison Cntrol Center-report

on phenylpropanolamine is unduly and inappropriately pessiMiatic. /- . do not believe that a valid extrapolation-can_be made_from the actual. _data to the report's sssieuste of 10,003 phenyIpropanolamine problem

. . . cases nationally. . . . :

; .

. . , 3. The cases reported to the Poison_Control Center may or may_not he representative -of whit_is actUany happening nationally. _For example, the country's largest Poison_ControI Center, in New York City, ia_one Of the 90% of the country's_Citters not reporting its experience to the national office. _The 10rof theCenters reporting may not repre

sent a valid sample of the national situation. ,

4. Of the 328 cases with product_names, 64Z_involved_no_symptois of_any_ kind and the_majnrity of the remainder_did_not have significant symptoms. Overall; -most cases_were_telephoneinformational_ccemunications.__Only_: . h% involved a hospital contact. On the Poison Control Center scale from

mild(1) to moderate(2) to severe(3), the phenylpropanolamine reports _ were; overall, mild(1.4).

5. Over two fifths of the phenylpropanolamine reports were under 5 years of age and almost one third were between 14 and 18 years of age._ The former are presumed to be accidental and the latter may have been seeking a "high". If so, they would be disappointed because phenylpro panolamine is not an effective stimulant.The number of accidental cases is another reflection of the importance of the parent's role in management of medications in the home by always keeping medications unavailable to children.

There were about 200 suicide gestures or attempts.Not only did none of these succeed but there was no fatality in the entire year from

phenylpropanolamine, for any reason. . 434

the_temporary break-Celt orpeaking noted 6. 'The report does nOt_COnaider when_a substance firit-ieemployed by_larger';- by many epideOldIetiatt with the substance and ;;;;,,. Because_ of- unfamiliarity '-numbers of people; Mat becomes :, a barrage of mediapublicity; -when a substanie in emergency roomviaitsi_and there is oftin_a aharp_inc eeeee used centers, gostI* for reassuranen. calls,. reports to poison control And_reports declines. After a year -or tire, thenumber of such visits the 1979 reports -ofpherlylpropanolamine It may. well be, thereforei_that . temporary-cresting whith Willdiminish in ewe .incidents represent a 7! 'near future. U."."" ::`'.1.1'%"-': % ' pretaiMi_with_plienYlpropanolamine A subseantiiI contributor toreports of 7. "look- alike" produiti which mayinclude phenyl- is the proliferation of I-undiratind that in every state propanolinifie tIongWith_other_drugs.against n.dok-iIike" druggi therehas which has - enforced restrictions of probIeMi with pbenylpropanolamine. been a uniforM_decline in reports in combination If the state of Washingtonbans "look-alikte,.this bani phenomenon_noted in the preceding paragraph,should .with the cresting of phinyIprepanolamine mentions to "lead to a tharp_decline in reports . Poison Centre' Centers. , . '' .

Charles Winict, Ph.D.

CW: kj 435

STATEMENT OF THOMPSON _MEDICAL COMPANY TO THE SUBCOMMITTEE ON HEALTH AND LONG-TERMCARE SELECT COMMITTEE ON AGING_ U.S. HOUSE OF REPRESENTATIVES

Mr; Chairman and Members of the Subcommittee:

The SUbdommittee kindly offered toThompson Medidal

Company the opportunity to testify at the hearingheld on July 21; 1983, on the Safetyand Effectiveness of OVer-the-Counter Drugs and the Elderly;

Thompson Medical it A leading distributorof

over-the-counter weight control productscontaining

phenylpropanolamine hydrochloride (PPA). These products are widely and succestfUlly usedto suppress appetite, thereby

lower food intakei and help reduceexcessive weight, which is well understood to be a Majorcause of disease and premature death.

Thompson Medical alto dponscrs: andsupports scientific research in the field of weight control. For this reason, it offered its time before theSUbcomMittee to a panel of eight medical expert witnesses; allof whom have undertaken studie8

Of PPA, which is an ingredientof the most pOpular weight control products as well asmany cough/cold preparations; 436

AS the experts havetestified; PPA has been safely It has received more used in the United statesfor 50 years. drugs, and clinical study andevaluation than many prescription far more than most otherwidely used over-the-COunter demonstrates that PPA medications. All this eVidence clearly when used is a safe and effectivemedicine for weight control, as directed. In addition to the experttestimony presented at the

hearing, Thompson respectfullysubmits the following comments

Of its own to theSubcommittee.

the Elderly p1; PPA is Not a Problem for

submitted to the The supplemental statement at the Subcommittee by CharlesWinick, Professor of Sociology showing that City University Of NewYork, documents his studies

fewer than one percent ofthose who use PPA weight control products are over 60 yearsold. His statement also documents not his conclusion that theweight control indUstry dtieS

advertiSe or promote theseproducts among senior citizens. Medical Company Moreover, as ProfessorWinick notes, Thompson under age 18 labels its weight controlproducts to advise those advice and or over 60 not to usethem except under the supervision of aphysician: 437

The Proprietary Association, theOTC dtUg trade

association of which Thompson Medicalis a member, hot

documented the fact thatconsumers, including the elderly, elo

read such label warnings and heed theM. ThoMpson Medical fully

supports the Association's educationalactivities to alert the public to the importance of labelsand the taking of proper

dosages. The fact that theseproducts are so little used by

the elderly is also evidence that theelderly do read and follow such label warnings;

Fihally; Thompson Medical carefullylabels its PPA products to warn againstuse by those WhO have high blood

pressure, diabetes, heart, thyroid, kidneyor other disease or are being treated for high blood pressure or depretsion. Our product labels also warn against using PPAwhile pregnant or

nursing, except under the supervision ofa phytidian. Thompson Medical also supports consumer educationto encourage having one's blood pressure testedon a regular basis;

II PPA Presents No Safety Problem

A massive amount of clinical data hasbeen submitted to the Food and Drug Administrationdemonstrating that PPA is safe for use in weight control andcough/cold products.

The attached comments and replycomments submitted to the FDA by The Proprietary Associationduring 1982 document in 438 detail the more than 60 controlledclinical studies which These stddieS support the safety and/Or effectivenessof PPA. dethehstrate that PPA is not astimulant, has no clinically significant side effects; andspecifically does not affedt blood pressure, pulse, or mood. Mote recent studies at The JohnsHopkins University

School of medicine, which ThimpsonMedical has submitted to FDA and about which Mr. FrankFunderburk testified before the Subcommittee, confithi that PPA is safein currently-marketed dosages; It ShOUld be noted that, while manyof these studies included normal, healthy adults, anumber of them specifically included patients who hadpre-existing health problems; For example, the studieS referred to on page13 of the AsSOCiation's comments dated July 26,1982; were conducted with patients who had pre - existinghypertension. In one study

(Unger, et al.), the patients weresuffering from asthma as

well as pre - existing hypertension. In another (Bradley; who also testified), all the patients wereobese as well as

hypertensive. In a third (Noble, also awitness), the overwhelming majority of patients wereoverweight, and in a

fourth (Sebok, another witness), allthe patients were

overweight. Nor have the studies exclueedthe 7.Iderly: the Bradley

study, fot example; included patientsranging in age from 25 to 439

67, with a mean age of over 54 years; the Hoebel study,

submitted to the Subcommittee by Professor Coons, included

eight patients between the ages of 51 and 65, out of a total of

70 patients; and the recent Johns Hopkins studies included

patients between 18 and 55 years of age. All of these studies

concluded that currently-marketed dosage levels of PPA did not

significantly increase blood pressure or produce any other side effects.

Careful analysis of Poison Control Center and hospital emergency room data, as Professor Winick's testimony

demonstrates) also confirms that PPA is not a dangerous drug. Considering the billions of doses of PPA taken each year in

cough/cold and weight control products, the numbers of reported

cases (less than one-fifth of one percent of the "mentions") are miniscule.

A study of 70 reported cases by the intermountain

Regional Poison Control Center in Utah, which was submitted to the Subcommittee by Professor Winick) concluded:

The lack of serious side effects in either the cases

with only PPA or combinations of PPA with caffeine

raises questions about the serious reactions noted in earlier published reports." 440

far submitted to the FDA; The massive clinical data so country, together with 50 years Ofsafe use of PPA in this individual clearly outweigh the handfulof anecdotal reports of adverse reactions, most ofwhich, when analyzed, are attribUtable to frank overdoses orcombinations with other to the conclUsiOn that PPA drugs. This evidende can only lead used is safe in over-the-counterWeight control products, when as directed.

III. PPA Is Effective For WeightControl

The FDA Advisory Review Panelwhich studied over-the-counter weight controlproducts unanimously concluded when used that PPA was safe andeffectiVe for weight control, was based on as diredted. Their finding as to effectiveness eight double-blind stidieS;Which are described in The August Proprietary Association's attachedreply comments dated 27; 1982, at pages 11 through 13 and are onthe public record

Of FDA's OTC Drug Review. These studies demonstrated an average weight 108t per weekof 1.16 pounds with PPA; as

compared with .56 pounds perweek with placebo. It should be noted that the"placebo" regimen in these patient studies (like the PPA regimen)also included giving the physician. a 1250 calorie diet andexplicit directions from a _ diet Thus, in each case the"placebo' was accompan2ed by a 441

designed to cause loss of weight under the direction ofa physician. As a result, the much greater weight loss with PPA

is even more significant, because it is being compared 10:

another active program of weight loss, consisting of a reducing

diet and medical instruction as well as the placebo;

In addition to this substantial clinical evidence, a

survey study of nearly 4,000 consumers who used PPAi conducted by Professor Winicki reported even higher weekly weight loss

figures, averaging 2 pounds per week per consumer,or 25 pounds over a three month period.

IV. PPA Is Not A Drug Of Abuse

There is abundant evidence that PPA is not a drug of abuse. The evidence for this is cited and discussed in The

proprietary Association's enclosed reply comments dated August

27, 1982, at pages 8 through 11. These studies document that PPA is not a stimulant and does not have the abuse potential of

the amphetamines and other powerful stimulants. The recent

Johns Hopkins studies further confirmed that PPA does notcause euphoria, amphetamine-like reactions, or sedation.

The Federal government's most recent report from its Drug Abuse Warning Network ranks PPA 102nd among drug

'mentions,' considerably below such common drugs as aspirin, which ranked 50th. 442

The "amphetamine look-alikes" cr"street drugs;" which sometimes contain PPA in combination withephedrine and large amounts of caffeine, are nowillegal in most states and under instituted Federal laW. BOth FDA and the Postal Service have seizure actions against manufacturers ofthese illegal of the combinations. Thompson Medical, along with the rest legitimate OTC industry, strongly supportsvigorous law enforcement against the trafficking inthese illegal and

misleading counterfeitS.

V. The OTC Review

The FDA is currently conducting anextensive and

thorough review of all over- the - counterdrugs, pursuant to

Federal law and regulations.Among these are weight control

and cough/cold products containing PPA; Thompson Medical, with

the support of The ProprietaryAssociatiOn, has cooperated fully in the FDA's review of weightcontrol products. In its review, FDA appointed anexpert Advisory Review

Panel; which heard extensive testimony over aperiod of many

months and evalUated Voluminouswritten submissions. Thompson Medical appeared before the Panel and made anumber of oral and

written SUbMiSSions to it The Panel then unanimously fOUnd

PPA to be safe and effectiVein weight control products, when

ilod as directed; In addition; two other AdvitotyPanels 'nave

0 443

also recommended to FDA that PPA be consideredsafe for other OTC uses.

FDA published the Weight Control Panel Report inthe Federal Euister for public commenton February 26; 1982; and

The Proprietary AssociatiOn; With the assistanceof Thompson

Medical, submitted the attached commentsand reply comments;

Since that time, Thompson has continued sponSoringresearch on PPA and as new data has become available; has submitted itto FDA for the OTC Review.

Thompson Medical respectfully urges that FDAithe

agency charged by law and equipped to make thenecessary

scientific judgments about the safety and efficacyof drugs; is

the appropriate forum for weighing the medicalevidence .regarding PPA and all OTC modications.

Thompson Medical Company appreciates having this opportunity to present to the Subcommittee the scientifit

evidence on the safety and effectivehett Of PPAas it is currently marketed in legitimate over-the-counter weight control products.

4 4 6 444 N) THE PROPRIETARYASSOCIATION 1700 Penn SylvOnio Averwi N W Mathsnceen DC2000WP rone (20D 3034700

July 25; 1982

Arthur Hull Rayesi_Jr.I_M.D. Commissioner of Food andDrugs Dockets Managetent Branch(HFA-305) Room 4-52 ?Odd and_Drug_Administration 5600 Fishers Lane_ Rockville; Maryland 20857 -the- Counter weight ControlDrug_Products for Over Ruman_Use; Establishmentof_a Monograph; Advance RUletaking, 47_Fed. 8456 Notice of Proposed 81N-00 n et-teq. (February25-u-11-824-; Docket No.

Dear Sir: contained the above The February 25,1.982 Federal Register of3Report and Proposed _ proposal, which Consists Miscellaneous Monograph of theAdvisory Panel on OTC convened by the Foodand Drug Internal Drug Products, OTC DragReview.__Interested hdministration under its comments by July persons were invitedto submit written 25, 1982. filed on behalf of_TheProprietary _ These comments ate trade-association, the active Assediation;_a 101- year -old and members of Which areengaged in the Manufacture distribution Of nonprescriptionor over -the- counter Members of the_Associationare Medicinal products. Drug and_Coometic Act(21- SUbject_to the Federal Forid; and affected by U.S.C. 301, et Eta.)and are interested in this proposal; comments_ These comments are notintended to supersede any individual members of theAssoCiation. that may be filed by

44 445

General Comments

1. Legal Status -o-fMonostapbs-

The Association notes its continuing position_that

Monographs issued under_the OTC Drug_Review are _ interpretive, as opposed to substantive, regulations. As to this point, the Association herein incorporates by reference: (a) its comments* dated March 4, 1972* on the Proposed Procedures for Classification of Over - The - Counter Drugs; and (b)_its comments, dated June 4; 1972, on the Proposed Antacid Monograph.

2. Exclusivity Policy

The Association also notes its- continuing position_that FDA lacks the statutory authority to prescribe exclusive lists of terms from which indications for use for OTCs must be drawn and to prohibit- labeling terminology which is truthful, accuratei not misleading, and intelligible to the consumer.

The Fair Packaging and Labeling Act 115 U.S.C. 1453(a)) requires_that an_item bear a_statement of identity. Section 5021e) of the Food, Drug and Cosmetic Act requires that the label of a drug bear the established name of the drug and, if there be none, the common or usual name. As applied to nonprescription drulL, these requirements are codified in 21 C.F.R. 201.51, which_cites _both acts as_its authority for requiring a "statement_of_identity° on the principal display panel. Section 508 Of the Adt authorizes the Secretary to establish official names for drug substances.

None of these statutory provisions reveal any Congressional intent to grant FDA the authority to legislate the exact wording of OTC labeling, such as indications for use4 and prohibit truthful labeling terms; Indeedi_if manufactarers_use_some of_the terms_ being prescribed by some OTC Review_Panels; their labeling may dell be in violation of Sec. 502(c) of the Food, Drug, and Cosmetic Act, which requires that label information be in such terms as to render it likely to be read and understood by consumers under ordinary conditions of purchase and use.

3. inactive-l-nsredient List -in-

The Association disagrees with the Panels recommendation (page 8473, third column) that inactive ingredients be

448

27-436 0 - 84 - 29 446

listed on the label. First, the listing of inactive- ingredients would be meaningless to all but a handful of consumers. Second, it may overstress the importance of such ingredients_ and obscure_far_more_meaningful information, such as directions_for use, warnings, and even the active ingredients. Third, it-may confuse consumers. Products which are similar in their purpose and even in the number and identity of active ingredients may differ widely_in the number and identity_of inactive ingredients. It is perhaps for -these reasons that current law does not require that inactive ingredients be listed, as FDA noted in paragraph 75 of the Final Order accompanying -the Antacid Monograph [39 P.R. 19862, 19871 (June 4; 1974)];

Specific Comments

1. The Proprietary Association_supports the Advisory P-ame--t -OlaggifiCatiOn of phenyIproanoIamine cogsvc-ed as safe and effective for -appetite-suppression- an-d-weightco The Association's recommendation_is_based not_only on the clinical evidence submitted-to the Panel_but also on the even more extensive clinical data wFich has become its Re0Ort.

The Association supports the Panel's recommendations as to both the safety and the effectiveness_of_ phenylpropanolamine hydrochloride (PPA; for weight control.

The FDA, in its preamble to the Panel's monograph, raised specific safety questions with regard -to- weight control products and requested further information;At the same time the agency stated that it did not find it necessary to take action to remove from the market products at dosage levels_which have a marketing history of use in OTC weight control drug products;The maximum daily- dosage levels in these marketed_products are an immediate-release dose of up to 37.5 mg and a timed-release daily -dose of up to 75 mg phenylpropanolamine, with the total daily dose not to_exceed 75 mg in either case (page 8466, second column];

The following comments seek to answer the agency's safety questions by providing the requested information, much of which relates_to products not before this Panel or was not available in time -for consideration by the Panel, which concluded its work on MarCh 2, 1979; 447

In its preamble, the agency has raised the following questions: a. To what extent may phenylpropanolamine hyurochloride induce hypertension in normotensive patients at the recommended dose levels?

b. To what extent may phenylpropanolamine hydrochloride aggravate pre-existing hypertension at the recommended dose levels?

c. To what extent may phenylpropanolamine hydrochloride interact with aspirin and other medications that inhibit prostaglandin synthesis at the recommended dose levels?

These questions are addressed below;

a; To what extent may phenylpropanolamine hydrochloride induce hypertension in normotensive patients at the recommended dose levels?

(11 The_panel had_substantial clinical evidence that PPA does not induce hypertension in normotensive patients.

The data submitted to the Panel on safety was inure than sufficienti by any standard. At least eight well7controlled__clinical studies were submitted to the Panel; -each cf which substantiated the safety of PPA as an anorexiant. These numerous supportive studies-far exceed the usual requirement of two well-controlled clinical studies. These studies are further buttressed by safe consumer use for almost half a century.

Ekhibit l contains brief abStracts of eight of the safety and efficacy studies made available to the Panel.

12) The_satsIty_reports_referred_to in the_preamble, which were7iiiii-ivailable after the_Panel's_report was Submitted, ShOUld not alter this conclusion. Nine reports were cited in the preamble as having been made available after_the_Panel's report was submitted. Two of these re-confirmed_the results of the_studies considered by the Panel that PPA does not induce hypertension in normotensive patients. These two positive reports are the study by Silverman, et 111ef. 71 and the studie_of_50 mg immediate and_sustirned release dosages by Cuthbert, Greenberg, and Morley Iltef. 6]; 448

Of the raining seven reportscited_in_the_preamble, six included isolated cases of individualadverse_reactions. These were the case reports of Rorowitziet al;_:_the portion of Ref._2 relating_to the one17-yeat=Old woman); PreWein; LeOnelIo; and_Prewin [Ref.311 Ring(Ref. 4); Peteron and Vaagdez :Ref_5);_Lee;Seilink_and Vandougen (Ref,811 andDeits :Ref. 9); _In noneof these_cases was Vince any possibility_of verificationof the actuai_dose of phenyIpropanolamine taken since thedose Was reported by the patient and not taken undercontrolled conlitionS; In at least two of the casesoverdoses were stated to have been taken 1_Ref.__2. relating to the I7,year-old,woman; Ref; 4). In five of the seven casea;"TrimoIets;" an_85 Mitanorqxiant_ marketed only in_Australia, wasused; In only tWO of the seven cases Was there anyfollow-dp to determine whether the_Symptomsreported_were_repeated under the same or different circumstances;_Six of the cases were simply anecdotal innature: Clearly; any drug; OTC or prescriptioni_has_the capacity tocause ileotyncratid reactions in a small number ofindiVidUal patients.

Only two of the seven adverse reportscited in the preamhIe_were_purportedly_of controlled clinidalstudies; both conlUdted by Horowitzet_al._l_Refs. 1 and 2). TO the first of these the agencyattributes "the most striking new finding" regardingelevation of blood_ _ pressure [page 8466;_secondcolumn).However both of these studies are inappropriate tothe agency's safety evaluatiOn of the recommended dose_in theUnited States because the adverse reactions reportedby_Dr._Horowotz were the result of testing the 85 mgAustralian product release; "TrimoIets;" This product was labeled as timed - hilt it is open to question whether_it_did in fadt Contain a timed-release tethaaiSm;__H;I_;_SilvermanL whose study was cited_in_the preamble !Ref.7);_received and analyzed a small numberof "Trimolets." As he_has_since_reported to FDA; SiIverman_foUnd_that the PPAin the product -was immediately soluble in water_and was_notin a sUAtaihed release form. (Set Exhibit 2; p. 2.) Silverman's analysis indicates that!TrImolets;!_Which had been -used to most_pf_the_instances ofreported adverse bltidd pressor' effects; delivered in abolus dose _ approximately two -and -a-,half times themaximum permitted immediate release dtite (37;5 mg); The_reported adverse reactions therefore were due to overdose; 449

131 additional evidence from controlled clinical studies that PPA does not cause hypertension in normotensive patients.

Additional studies, six published and 41 unpublished, which were not submitted to the Panel or referred to in the preamble4 support this conclusion. More than 3200 patients_were_included in_these_studies4 which were not submitted to the Panel because they became available after the Panel completed its work or were conducted on PPA used as a nasal decongestant. no,:cver, the dosage levels of PPA in the nasal decongestant studies were comparable to the_dosage_levels of PPA in weight control products; The published studies include the following:

W. E. Barrett, e-t reporting in Current Therapeutic Research 30: 540-6S14 November 19814 on a bioavailability study including_18 volunteers; found no adverse effects on vital signs; blood pressure; or -ECG; after giving 75 mg sustained action and 25 mg immediate release dosage forms of PPA.

StIvermani_et al.4_cepocting_in_Curcent Therapeutic Research 28! 1T5-944 August 1980i found no significant changes in either blood pressure or pulse values after oral administration of 25 mg phenylpropanolamine (od), with and without caffeine; in 37 volunteers.

R.S. Noble, writing in Lancet, June 19, 1982, described three large studies conducted is the past two years on more than 400 obese patients. (See Exhibit 3.) Dr. Noble wrote:

Data were gathered on a twelve-week, double-blind, placebo controlled study of 50 mg EPA three times daily...; a doable-blind placebo controlled study_of 50 mg PPA combined with-200 mg caffeine in controlled-release form; and a single-blind trial of 75 mg PPA in controlled-release form. All three dosages ceased no significant increase in blood pressure in more than 400 patients. 2 patients experienced noteworthy rises in -blood pressure after treatment with 75 mg ppA; but these increases were felt not to be drug related.

4 2 450

The mean pooled systolic and diastolic blood pressure in the 50mgx3 PPA/placebo study are shown in the figure.

' Our results confirm that PPA does not cause a significant increase in blood pressure even,when_the amount ingested j150 mg/day) is substantially higher than_the_75_mg dose. There Was, -on the contrary, a_ reduction in blood pressure as the studies progressed.

J.H. Black, Writing on The control of allergic manifestations: By phenylpropanolamine (propadrine) hydrochloride' in Lancet 54: 101-102, 19.37, reported no blood pressure changes or insomnia in 41 normotmsive patients given 48 mg doses of phenylpropanolamine as frequently as every three hours. None of five patients who received 384 mg within_two days showed greater blood pressure changes than 10 mmHg nystolic. In one hypertensive patient, 3 24 mg dosl was associated wita decrease in systolic blood pressure, from 175 to 160 mmHg, with na change in diastolic pressure.

ILE. Boyer; reporting on 'The clinical use_of_ _ phenylpropanolamine hydrochloride (propadrine) in the treatment of allergic conditions' in J- .- Allergy 9i 509-513,_1938,_statei that he administered 48 mg doses Of phenyIpropanolamine_very two -hours for five days or more with no effects on blood pressure; C.A. Mitchell/ writing on 'Possible cardiovascular effect of phenylpropanolamine and belladonna alkaloids' in Thet. Res; t9r,_47-53, 1968/ reported no pressor effects after_ Ming 511 mil doses of phenylpropanoIamine twice daily in 32 normotensive subjects. The as-yet-unpublished studies which demonstrate that PPA does not induce hypertension in normotensive patients are as follows: In an eight week, double-blind, randomizedstudy conducted by Rudolph Noble/A.-a./ Ph.1:,, in San Francisco, CA, 60 patients were divided_into twl_gcoups. Thirty_patients .were given 75 mg of phenylpropadoIamine and_200_mg___ _ caffeine, timed-releant (a), and thirty patient.; were given 75 mg diethylpropion, timed-release.There was no significant difference in weight loss between the groups. 451

No significant changes in either blood pressure or pulse measurements were indicated during the test periods in comparison with the baseline measurements.

Marianne Sebok,_M.D., Staff Physician at JFK Memorial Hospital, Philadelphia, PA, conducted a six-week, double-blind clinical study of 78 patients who were given either a sustained release capsule containing 50 mg phenylpropanolamine and multivitamins or placebo.__The study demonstrated statistically significant weight Ioss for the active medication group at all measuremept intervals. No clinically significant deviations were noted -in -blood pressureAsystolic, diastolic) and pulse and there were no significant side effects;

Stanley L. hltschuler, M.D., Medical College of Pennsylvaniai conducted a double - blinds 6-week clinical study of 64 patients who were given either four phenylpropanolamine drops (25 mg) or placebo_drops (tid). This study demonstrated statistically significant weight loss at Week 6 for the phenylpropanolamine compared to placebo at the .n4 level of confidence. No clinically significant_deviations in blood pressure (Systonc,_ diastolic) and pulse -were noted, nor were any significant side effects reported.

Hoebeli Krosnicki et a1.4 Department of.Psychologyi Princeton University, conducted a double-blind, crossover study -in which 6- patients took a sustained release 75 -my phenylpropanolamine dose twice daily or placebo c.Apsules. Experimental and placebo groups were reversed after two weeks so that the patients served as their own control. Body weighti_pulsei blood_pressure and fasting blood glucose levels were recorded three times- weekly. There was no significant change in either blood pressure or pulse rate during the 4-week study in which the prediabetic_patients_received_twice_the_daily_reeommended dose of phenyipropanolamine;__ The_patients! signs were - monitored in 12 separate office visits during the period of the clinical evaluation.

In_a bioeguivalence study at the Massachusetts College of Pharmacy and hilted Health Sciences, 75 mg __ phenylpropanolamine (od, SR) was compared tO 25 mg (tid, IR) in 18 volunteers. No significant blood pressure effects were reported.

In a study of 12S -male and female patients by_hivin P; Wenger, M.D., tablets containing 50 mg PPA (SR), 25 mg pyrilamine ma Bate, and 25 mg pheniramine maleate were

4 452 compared_with placebo for_effectiveness as a nasal decongestant; Eighty patientsi including all the placebo_ patients, were double blinded; Blood pressure evaluations were taken at two and four hours after dosage. Overall, there was no major change in blood pressure at the 95% level of confidence; _The_major side_effect reported_was drowsiness,- with -56% of the_PPA_patients reporting at least some drowsiness and 38% of the placebo patients. (OTC Volume 040-151) The following information was provided_to_the Association by a membeit company; It -is -our understanding that the company is submitting thit; information to ?DA in greater detail.

Between -1971 and 1975i blood pressure determinations were recorded in seven studies-of healthy adult volunteers to evaluate the bio-availability of PPA from various fo:mulations. Generallyl the studies were conducted as crossover trials_comparing_sustained-release tSR) and immediate-releaseAIR) formulations administered as single A total of 76 volunteers were inciaded in the studies, and they were administered 211 test doses of PPA. 7lood pressure and pulse rate, wert de.termined before and on several_occasions_after admidistratiOn_of i;tch test dose The following test doses were

mg IR doses were administered 35 volcnteers on a_single occasion during threo st11-3;to (1:0441 (12 received 150 -mg as a single_dose_xt23 received 150 mg in divided doses over 8 hours); 150 mg SR doses were administered o 48 volunteers on 60 occasions during four studies (#2,3i4,5); 100 mg IR doses were administered to four volunteers on a single occasion during one study (#4);

75 mg IR doses were administered to 48 volunteers on 50 occasions during four studies (#1,2,4i5);

75 mg SR doses were administered to 12 volunteers on a single occasion during one study (#1);

50 mg IR doses were_ administered to_12 volunteers on a single occasion during one study ;113);

35 mg IR doses were administered to 12 volunteers on 24 occasions during one study (07). 453

Clinically significant increases it blood pressure were detected only following administration of 150 mg immediate release PPA, and only in five out of the 35 test doses. EVen_in the_five_casesthe increases_were transient_and blood pressure returned_to baseline levels during the observation_periodS without medical intervention. The increases also amounted to only 10 to 30 mmHg, with the maximum reading of 100 mmHg diastolic.

Ten- investigators- submitted reports on a total of 337 adults and 51_children (age 12 or under) taking sustained release cough/cold capsules containing 50 mg PPA1 4 mg chlorphentramine maleate ICPM)i and 0.25_mg_belladonna alkaloids. Side effects_were_reported in -24 (7- percent) of_arluIt patientn, including drowsiness (11 patients), urinary retention (1 patient), and nausea (1 patient). There were no reports of elevated blooi pressure. No side effects were reported among the children treated.

Two- hundred- fifty- patients were given the same 50 mg product. Side effeCts were reported by 54 of these patients. There were no reports of elevated blood pressure.

One_hundred fiftysix patients were given the 50 mg product. Side effects reported were: dry mouth (1); headache (1); and drowsiness j2). Medication was not discontinued in any of these patients because -of -side effects; There were no reports of elevated blood pressure.

Twenty patients were given the 50 mg product. Side effects included. drowsiness Ms increased_eye_itching and congestion (I): 'burnt taste_in stomach! (I): nosebleed (I); MediAtion was not discontinued in any of these patients. There were no reports of elevated blood pressure.

In a comparative study of this product and a product containing APAP 195_mg, pyriIamine maleate 25 mgi caffeine I5-mg,-ephedrine sulfate S mg, and phenylpropanolamine hydrochloride 25 mg, 25 patients took the 50 mg PPA product and 23 took the 25 mg PPA product,Side effects were noted. There were no reports of elevated blood pressure;

One hundred eighty-eight patients were given twice daily sustained release_cough/cold capsules__ containing 50 mg PPAi 4 mg CPM,_and 0.25 mg_belladonna alkaloids. Side effects were observed in 13 of the patients studied. Dryness of r.;outh - a reaction to the 454

belladonnas - was_reported by five patients._ Upset stomach occurred in a patient being treated for ulcer symptoms. Two patients reported ejitterinessu and 'irritability' and had the drug discontinued. One case of urinary retention_developed in an elderly male tage 72). Thera were no reports of elevated blood pressure; In another study, 111 patients were given the same 50 mg product twice daily. Dry mouth was noted in two of the patients; No other adverse effects were noted. Eighty patients were given the same product twice daily for a period of two to six days. Side effects noted were: drowsiness (10): dry mouth L411 urinary retention 11): and nausea (1). There were no reports of elevated blood' pressure Eighty-four patients were given the same product twice

datlg f.c. one to 14 days, There was one report of dry mouth ,tre no reports of elevated blood pressure.

Tnirt= six patients took the same product. No side cf'7e,:ts were reported. Eighty-eight patients were given_the same product twice d4i1y. There were no adverse effects noted; Fifteen normal volunteers received the same product for a period of six months. Pre -drug data were collected two weeks prior to dosing and - one -week prior to_dosing; Dosage was one capsule twice daily._ Two volunteers -did not complete the st.141v, for nor-medical reasons. There was no control group ts of this study showed that the product was _;:atii fo4 _1Qng-term use. Side effects noted - were: blurring of- vision (1) and_abnormal_SGOT4 probably due to low-grade_henatitis II); _Diastolic blood pressure averages remained ,liform throughout the study. SyStolic blood pressure averages showed -a slight increase (at Weeks 12,_13 and 20)i though_the mean systolic pressure -was 125.5 mmHg. At Week 2Simean_blood_pressure was 120.5/75 mmHg. Pulse rate dropped early in the study; although this decrease did not coincide with the systolic hlood pressure change. /t was felt that all of the changes_seen could_be_related_to the volunteers' activities during different phases of the study.

In a three-year study evaluating the same 50 mg product versus_placebo* 450 patients participated. Of the patients taking-the medication, 11;5_percent developed possible side effects; Of the patients taking placebo, 455

8;2 percent experienced possible adverse effects:There were, however, no reports of elevated blood pressure. A double-blind study of 178 patients with symptoms of acute coryza was undertaken comparing the_ef4ects of a product containing phenylpropanolatine HC1 71 mg and chlorpheniramine maleate 8 mg, in a sustained-release capsule' a sustained release product containing pPA 50 mg* CPM 4 mg; and belladonna alkaloids 0_;25 mg; and_placebo. Adverse reactions were reported by 10 percent of the patients taking the 75 mg PPA product, 12 percent taking the 50 mg PPA product, and 9 percent taking placebo. There were no reports of elevated blood pressure.

L.S. Cobin reported that mean blood pressure and pulse rates were not affected uy 50 mg SR PPA (bid), 0.2 mg belladonna alkaloids Ibid)_, a combination of the above* or placebo in 20 normal volunteers;

Dt. RiChatd mulboott found no reports of eleVated bleed pressure during a crossover study on the comparison of placebo aLd a sustained release product containing PPA 50 mg; CPI 4 mg, and belladonna alkaloids 0;25 mg on intraocular pressure in normal glaucoma patients;

J. Colemoce conducted an open study using 10 volunteers who received 75 mg PPA Ibid4 SA) for 8_ weeks. No_ clinically significant -blood pressure or pulse effects were seen; (NDA 12-685; OTC Vol. 040012.)

9. 9aibach conducted an open study using 15 volunteers who received 50 mg ppA (bid; SA) for 6 months_. No clinically significant- changes -were seen-in bloodpressure or pulse values; Slight increases In-systolic bloodpressure -were seen in weeks 12; 13; 18 and 19; (NDA 12-695; OTC Vol 040012.)

An open; crossover bioavailability study of 150 mg phenylpropanolamine (odi SA); 75 mg phenyipropanolamine (od, IR), and 50 mg phenylpropanolamine (od, IR) was condectedi using 12 volunteers. Ho significant blood pressure effects were recorded. (NDA 18-099.)

b. To what extent may PPA agg,avate pre-existing hypertension at the recommended dose levels? 456

Cli-finical studies demonstrate_that PPA does not m,g tetridiOn. Two_clinical studies have come to this conclusion, one publisherland one unpublished._ D.L. Unger, L. Ungt::: and D.E. Temple reported on the !Effect of an anti,azthmatic compound on blood pressure o- asthmatic patients" in Linia,211112aly 25: 260 - 251,__1967. Doses of 25 mg phen:qpropanolamine were given three times a day to 21 asthmic_hypertensive patients _for_one_to three weeks. Baseline blond pressure averaged 166/102i within one hour after admnistration, the average blood pressure was 164/102. The median blood pressure pre-dosing was 164/104 and after dosing_168/102. Five patients had a 10 mmHg elevation in_systolic blood pressure_and five had a decrease of 10 mmHg. Four patients had a_10 mmHg _ _ elevation and four a 10 mmHg decrease in diastolic blood pressure. None of the patients studied had to discontinue use_of phenylpropanolamine because of side effects._ _Th,t authors concluded that phenylpropanolamine_produced_no _ significant changes in blocid pressure at the time of peak blood levels following administration of 25 mg doses.

In a pilot; single-blind, crossover study conducted by M.H. Bradley, M.D., on ten exogenous -obese patients wP': controlled hypertension, no clinically significant char): 4 in _blood pressure values were seen in patients who wet given_25_mg PPA (ttd), placebo, and 75 mg PPA (od). (See Exhibit 4.) c;__To what extent may PPA_interact with aspirin and other medications that inhibit prostaglandin synthesis at the recommended dose levels? There_is_abundant evidence from the long use of ?PA/aspirin combinations in -OTC cough/cold products that such combinations do not induce hypertension.__This_haa_ been-tenfirMed-conclUSiVel- b- clinical_ studies of as irin .1WWW1C. V..-W:MMITI.T.211:=1"7"271°. ALTnation Wit phenylpropanolamine. The agency's request for information on_this_questico arises from a report on a single patient. Lee, & Vando.igen (Ref. 9] reported severe hypertension in a_ single patient ..eking an 85 mg dose of phenylpropanolamine together_with_a 25 mg dose of the non-steroidal anti-inflammatory medication, indomethacini although

459 457 neither of the drugs was associated with hypertension in the patient when given alone. The authors of thit single patient report apparently postulated that the decrease in prostagiandin_levels due to indomethacin concomitantly reduced the inhibitory- action on catecholamine release._ _ As a result, the administration of phenylpropanolamine may have invoked a greater than expected release of catecholamines; resulting in profound vasoconstriction and a- increase in blood pressure.

The record indicates that hypertension is known to occur from the clinical use of indomethacin Wennmalm, _a_Influence of Indomethacin on the Systematic and Pulmonary

Vascular Resistance in Mani _ 141-145; 1979; 1982 Physicians Desk Refiiince). However; no such data is available with regard to aspirin. Furthermore; the known long-term concurrent use by patients of aspirin and phenylpropanolamine to alleviate the- discomfort of_the_common_cold has_not indicated evidence of any significant hypertensive responses;

There have been several largei well-controlled studies which have examined the potential for chronically administered aspirin to influence blood pressure; no hypertensive effect of aspirin has -ever been demonstrated (The Coronary Drug Project Research Group, Aspirin in Coronary Heart Disease, J. Chron. -Dis29: 625-642, 1976; A.A. Cooper;_°Efficacy of zomepirac_in Oral Surgical Pain, J. Clin. PharmacoI. 20: 210-242; 1980).

There are a number of leading non-prescription cold and allergy_ products which have combined aspirin with phenylpropanolamine tn_addition to other ingredients (Handbook of Nonprescription Drugs_i_Sixth Edition; Amer; Pharm. Assoc.; WaShingtOn; D.C. 1979; pp. 107-112); Many nonprescription and prescription combination products have been used safely for many years in the United States as well as in Europe; If there were_any__real potential for interaction between- aspirin and phenyIpropanolamine or any other sympathomimetic, it would certainly have been obvious. -vet the market experience has been remarkably free of adverse reactions. A consortium of cough/cold product manufacturers made_a presentation to the Cough/Cold Panel on September 1; 1974, in which they submitted the following data on adverse reactions per 100,000 packages of various leading combination products: 458

Adverse Reactions Total Packageo Combination Per 1000000-- Soli

PPA and 0 ;282 to acetaminophen 10 million

PPki chlor7 0.109 10 million to phentramtnei and 50 million aspirin

plphi chlorphentr- 0.091 1 million to amine and calcium 10 million carbaspirin This admirable record of reported adverse reactions over the years of use of these products indicates how remote is the poo3iOility of signifiaant occurrence of the adverse reaction in goetion; Clinical evidence that a therapeutic interaction between aspirin and PPA does not occur is well demonstrated in a 30-4Ay_human_study_; (Coughi_Coldi_Asthmei_Bronchodilator And Allergy Panel Reporti F.11_;_Sept; 9, 1976; OTC_Volume 040298 (1971)). This doUbTiZlind; clinical -trial employed a total patient population of 68 (65 male; 3 female)i and incladed four identical-aopearing tablets of different composition provided_to sabjects by_random_ assignMent. Dosage Wag two tablets taken 4 times daily

Formula Code Composition tablet Total Daily Dose

SHP-78 ASA-325 mg 2600 mg PPA- 25 mg 200 mg

SHP-79 PPA- 25 mg 200 Mg

SHP-80 ASA-325 mg 2600 mg

.SHP-82 Placebo A total of_25 patients_completed 30 days_on thecomplete regimen 'Astro SHP-78 while three other_groups of_nine patients per group completed the 30-day therapy using the other three dosage forms. subjects not consuming the assigned dosages were dropped from the study. 459

Formula Code S4 P-74. SHP 79 sap-sa SHP-SZ

Subjects Assigned 34 11 11 12

Subjects Dropped 8 2 2 3

Subjects Completed 26 9 9 9

Ail_subjects_were_provided_wirh clinical and- laboratory- evaluations includinj blood cbemistry, urinalysis, blood count, blood pressure, pulse Ldtes. body weights, and oral temperatures. Pulse and blood pressure were monitored on Days 0 (day prior to_3dministration);_7, 15; 22 and 30; One patient in the ASA_group_exhibited a dramatic increase in pulse rate on Day 30. This was attributed to personal problems on that day specifically and was not considered to be drug-related. The conclusion reached upon completion of the study was_that no evidence of_ drug-related toxicity was observed or determined.

This stilly therefore provides conclusive evidence of a lack of interaction between PPA and aspirin; __ AdditionaIly,_it provides further support-for the proposition that P?A does not adversely affect blood pressure. Subjects in this study ingested -a total of 200 mg PPA daily for 30 days in individual 50 m3 doses. Tablets were not sustained_release; A_total cf_35 subjects completed the 30-day regimen taking PPA; On the basis of the dosage employed, the number of subjects enrolled, and the length of time they received a combination of PPA with the non - steroidal antiinflamatory product aspirin; no adverse effects relative to blood pressure or btlin 4ita1 signs were reported.

Summary

The data that was before the Panel, and the more extensive data which has become available since the Panel completed it work; constitutes_a_massive_amount_of scientific evidence drawn from 60_controlled cIinical_studies involving more than 3,700 patients. This data demonstrates that PPA does not induce hypertension either in normotensives or hypertensives or when it is in combination with aspirin_. _This_data, together_with_almost

50 years of_safe use_of_PPA in this country. clearly _ outweighs the handful of adverse reports referred to in the agency's Preamble. 460

2. The_ Proprietary Assoc late_._ -tedOmmerids-that the FDA accept the Panel' s _recommendati-on labeling for the combination of phenylpropanolaminehydrochloride ia7Eilletne;

The_ Panel Report recommends Category I statusfor the combination of phenylpropanolamine hydrochloride and caffeine if labeled as an_°Ancrectic/Stimulant!_tpage___ 8476, first column). In its preamble FDA invitee_comment_ on alternate or consolidated labelwarnings and directions for such combinations, noting_that a discrepancyekidtd betWeen the directions for use_of caffeinein thisand another current proposal to the agency (page 8469,first column). The warning proposed in_the_Te;,:re FinalMoncdgzaph of the Panel on Over- The - Counter tii)time_Sleep-Aidand_ Stimulant Producta (Sleep -Aid- Panel) waa,_"For_occasional_ use only.* 15 340.50(c)(2)1 43 1?-;-R;_ 25602); _However, the warning- proposed by the Miscellaneous Internal Panel for Weight Control Products_specified daily doses for up to three months. 357;550(d)t page 8484, second column). We do not believe the agency's concern aboutthis discrepancy is warranted;_ Caffeine_in_combinatienWith phenylpropanolamine hydrochloride in weight control products is intended only as adjunctivetherapyi_used_to mitigate the lethargy that may accompany areduced diet regimen; ks the Panel Report stated, the Panel_had to decide_wherhei: or not a significant portion -of the dieting population becomes fatigued while dieting. _Sased_upor; its_ professional experience the Panel concluded that such a significant_patient_population doet exist and that the combination of_phenylpropanolamine hydrochloride and caffeine_ meets_ the three criteria of FDA's combination policy; (Palle 8476, first and second columns).

Ay contrast; caffeine in stimuIant_products_isintended to "help restore rental alertness or_ wakefUlnessduring__ fatigue or drowsiness° whenever theseconditions occur. (S 340.3; 43 P.R. 25602). In additiOn; the quantity of caffeine intie weight 461

control products is inhereatly limited to 600mg per day by the current and tecomnended maximum frequencf_of_dosage of three times a_day. Againi_by contrast, when caffeine is used_as a_stimulant_product, the recommended maximum dosage can_be as much as 1200 mg per day (100 to 200mg not more often than every 3 to 4 hours).

Thetefore, it is appropriate to require the more __ _ restrictive darning on_the caffeine products for relief of general fatigue and drowsiness;

Moreover, the amount of caffeine involved in combination with phenylpropanolamine hydrochloride in the weight controlproducts is_100_to 200_mg. It is essential to note that this is_only the equivalent of approximatelytwo cups of coffee. In these dosages, caffeine has been found to be safe, either alone or in combination with other _ substances. by three other OTC advisory panel tepw7t11;in addition to the Weight Control Products PanelReport. The most_recent ofthese-other panel reports, on Orally-Administered Menstrual Drug Products, summarized all three panel reports as follows:

712) Caffeine; The Panel concludes that caffeffiri7qinerallir recognized as a safe and effective diuretic for OTC use in the doses noted below in relieving water accumulation symptoms of the premenstrual and menstrual perod.

'(i) Safety. The toxicity of caffeine has been reviewed extensively by the Advisory_Review_PaneI on OTC Sedative, Tranquilizer, and Sleep Aid Drag Products in a report published in the FEDERAL REGISTER of December 8, 1975 (40 FR 57292). That Panel discussed, in addition, the mutagenic effects of caffeine in detail. It found caffeine to be safe "__When_used_in the recommended oral_dose of_.I00 to_200 milligrams (mg) notmore often than every 3 to 4 hours.' FDA concurred with -the Panel in the tentative final monograph published in the FEDERAL REGISTER of Sane Iii 1978 (43 FR 25544).

The Internal Analgesic Panel also reviewed caffeine: fot its analgesic properties in_the__ FEDERAL REG/STER of_July_8, 1977 142 FR 35346) and expressed its agreement_with the conclUtioht of_the Advisory Review Panel on OTC Sedative, Tranquilizers and Sleep Aid Drag Products regarding the safety of caffeine. This Panel

#64 x."(fl 27-436 0 - 84 - 30 462

agrees with the above reports and concludes that caffeine is safe as an OTC diuretic for relieving water accumulation symptoms of the premenstrual and menstrual_period in doses of 1100 to 200 mg every three to_four hours; Second information CoPY-F-O-C-Orally Administered Menstrual Drug__ Fro acts- Report, Septetber 22; 1931; pp; 55-56;

In its final_meeting_on_October 15-174 1981; thePanel, in its review of the Pienstrual_Drug Products Report; added to this conclusion its approval of a combination of caffeine with a menstrual product. Moreover, it did so ;based On the same_rationale it used for its approval of the combination -3f phenylpropanolamine and caffeine in weight control products, that is; relief of fatigue; The minutes of the Panel meeting state: The Panel was made aware that caffeine is contained in an- OTC menstrual drug product_fa _ combination product) which contains a claim for the relief of fatigue in the premenstrual period, Because the Panel has already recognized that fatigue is a component of the premenstrual syndrome and because caffeine_has already been_ classified as a Category I stimuIant_by another parel, this Panel concludes that caffeine is -an effective menstrual drug product ingredient fot the claim of relieving fatigue occurring in the premenstrual period."_ Summary Minutes of the Fartv-Sixth- Meeting-of-the OTC Miscellaneous internal Drug Products4kaael, October 15-17; 1981; p; 5. Finally, it is noteworthy that even In FDA's current inguiry_regarding the use of caffeine -as an added -food ingredient; the agency has specifically exempted from tnat inquiry the presence of caffeine in coffee and the use of cafteine in drugs;

3_, disacrees_with the P-anels-con-c-1-u-s-i-o thd'r, and minerals should not be constituents-of atul otiOdUCts;

The Panel report notes that some weight control products now on the market contain a number ofvitamins and 463

minerals in addition to their weight control active ingredients. The Panel also states its bel If that it is the responsibility of the consumer to determine the

dietary cegimen_to follow in order to maintain_a - _ welI-baIancedi Iow-caloric diet' (page 8472, third column).

We share the Panel's belief in this regard. However_i we strongly disagree with the Panel's conclusion which is purportedly based_upon this belief._ The Panel somehow leaps from its belief about a well-balanced diet to the conclusion that 'therefore, the n5dition of vitamins and minerals in combination with the weight control active ingredients] serves no useful_ourpose_for those following a well-balanced diet_and_vitamins and minerals should_ not be constituents of weight control drug products° (id.). The Panel's conclusion does not follow logically from its premise and also conflicts with one of_the Panel's other recommendations, which FDA strongly endorses in the preamble, that "a reduction in total daily caloric intake below the energy output' must accompany weight control drug products in order to achieve significant weight_ loss (page 8468, third_column;_page_8469, first column; page 8472. second Ind -third columns). Again, we agree with this reconmendatiOn.

Howeveri a consumer who follows this label direction_ and reduces_ caloric intake below the energy_output_may, no matter how welt - balanced the_resuItant diet,_aIso reduce the amount of vitamins and minerals previously needed to maintain the consumer's body weight and frame. The recommended dietary intake of essential nutrients, particularly vitamins ani_mineralsi_may be difficult to achieve during caloric reduction, since in many foods vitaAns and minerals are present only in low concentrations. Under these circumstances it may be desirable to provide the consumer with the option of _ obtaining a vitamin and mineral_ supplement in combination with phenylpropanOlamine hydrochloride appetite suppressant in order to replace those vitamins and minerals lost as a result of lowering food intake.

Finally, vitamins and minerals which are dietary supplements are foods and should be treated as such in this combination. Combinations of cosmetics and drugs are permitted so long as each complies with- applicable-- regulations. The same rule should -be applied to the _ combination of vitamins and minerals with weight contrdl active ingredients. The Bureau of Drugs should impose no more stringent requirements on such a vitamin and mineral 464 iloantament than does the Bureau of Foods.

!:t is in the best interest of good medicine and of the -_ Consumer to make generally available the greatest possible variety of safe and effective medication. Manufactiiters should therefore_not be prohibited* contrary to the Panel'S reconnendation, from offering such a rational combination of PPA and vitamins and minerals;

The Proprietary Association recommends that the FDA_ 4.reject some-o-f-the-Pmendations with regard to catmor II la-be-Una, The Association recommends that the following claims recommended by the Panel to be placed in Category II__ _ should instea,1 be placed in Category I. We believe that some_of these claims represent the same claims which the Pane/ recommended be placed_in_Category I_but_are stated in language that is more readily understood by_the__ consumer. Othert are trUthfUl statements or, at most, amount to acceptable puffery. Indeed, the Panel itself stated that it 'is aware that there may be other terms that would be_acceptabie in_expressing the same Category I indidations' (page 8473; first column). These thirteen statements should not be classified in Category II because_ they do not* in fact* lead to use of the product other than in_the manner_recommended_OY the__ Pahel as generally recognized as_safe and_effective.Each of these Category II claims is discussed below: a; 'Contains one of the_most powerful diet aidsavailable Without prescription' (page_8476, second colUmni. This is a true statement: The Panel- recommended only two substances - - phenylpropanolamine hydrochloride -and benzocaine - - for Category I as safe and effective; b. cbatains one of the_strongest diet aids_available without prescription' (i1;).; Like cIaim_'a", thisis -a___ true statement for products containing phenylproparolamine. c._Encouraces water loss_with_a_gentle diuretic' (i-d.).

This is a tree- statement-for products_containing_ _ caffeine. Caffeine has been recommended for Category I as a diuretic by the panel reviewingorally-administered menstrual drug products and in Category I as a Mild xtimulant_by both_the_Nighttime__Sleep-Aid_and Stimulant products pan4I and the panel reviewing menstrual drug 465

products. h fuller discussion appears aboveon pp. 17-19 in section_2 relating to the labelingfor caffeinetphenyIpropanolaMine combinations.

d. 'Essy-to-follow_reducing plan_ builtaround food you_ love to eat._ You will_eat well_butless and lose weight without_going_hungry' (id;); Clinical studies submitte.1 to the Panel demonttrateweight_losswhere_caloric intake_ has been reduced in accordance withdiet_plafts recommended along with these products; _Thesediet pleas contain a wide variety_of nutritious foods,limited only in quantities, not to the breadth of thearray of foods_ specified; Thit labeling should certainly beallowed on prodUCts UhiCh are packaged witha diet plan;

e. 'A unique way to help your overweightpatient eat_less" (id.); This is a true statement becausethese__ products involve the consumer's using-a specific, approved_ medication to reduce_appetitei_tatherthan regairiny the conoumer to sinply try to follow exhortatiOhtto reduce calories without the assistance of medication.

g; 'NoY enjoy a slim,_trim_figure. Losepounds; Reduce inches' ipage_8475, third_column);These_claiMt are lay lescciptions_of goal-oriented producte andare helpful -in encouraging proper compliance with productinstructions; h; 'Lose weight starting today,_Lookyoar_best, feel your best" (id.). _This is_a true statement; Wheh caloric intake t reduced below energy requirements,the body begins_to use up stored fe or energy. The claim does not refer to any specific ant of weight_loss on_the_ first day. While the amouut_may be relatively small;it is nonetheless a_start_andionce the process starts, the end result is closer -than before. Like claim "g," these_ claims are lay descriptions of those goalsand_are_helpful in assuring proper compliance withproduct instructions; i. 'The delightful aid to_appetitecontrol' (id;). Except for 'delightful'_ this is the sameas 'An aid 171 the control of appetite,' recommended forCategory I by the Panel 4page_8475, first column/ 1 2(5)1._The_addition_of "delightfill° is harmless pufferyi_follyjustifted_by the fadt that the_recommended diet plans enclosedWith the products contain a broad -array of foods. The reasoning for this is the same at for claim 'd' above. j:- 'Delightfully delicious,_scientificallyformulated to help you control your appetite_gutcklyi_pleasantl(page 8475, second column); As in the case of Claim .1", above, 466 the addition of "delightfully_ delicious"is, again, justified by the breadth of_variety in thefoods included in the diet plans enclosed with these products. The phrase 'scientifically formulatt!S" is truthful. k. "A most pleasant_aid to help_yculose weight' (id.); AS in the case of claims "d",_'"i! and "j",above. rge phrase 'most pleasant' is_fully_justifiadby th 'de variety_of foods permitted by the diet plans en 2d with the products. 1. 'Trim pounds awl inches without_crash_dietsand strenuous exercise' (id.). This_is a true statement_and is also properly goal-oriented, likeclaims 'g' and 'h."

M. 'A modern aid_to appetite_control_forpeople who love to eat" 04.). Thig accurately describes_in lay termsthe target population of thOge who, withoutthis aid, would eat larger quantities of food. o. "Reduce to the weightand_size_you want_to_be (Id.). A3 in the case Of claims 'g,'"h,!_and "147__it is_ important in ensuring proper compliance_with product instructions for the consumer to keep thegoals in miaA. effedtiVe_easy-to-follow_diet_plan_that lets you q. 'An enjoy eating delid1bus nutritious- foodseveryday as you lose_weight" (id,). Like claim 'd,' this is a truthful statement. t. "Ehables the obese individual- tolose_ueight in the most comfortable manner by decreasingthe desire for_ food" to_lose_ (id.). These products enable obese individuals wiht in the moat comfortable manner' becauseappetite is reduced_for_greater_quantitiesof food than permitted by the enclosed diet plans; a; 'Hunger pains are spared and alOW_catIorie reducing _ diet_ may nowbe_more_easily tolerated"{id.); This is a trilthfUI statement; describing_accuratelythe process by which theSe product thieve results.

Claims "r" and "s" not only truthful but describein detail the manner ..ich the produdt Works; In_fact, thet statements_ explain to the consumer the 'This reasons for the P 21's ; :oposed_statement: product'e effectivended it directlyrelated to_the_dgree to which_you_reduce your usual A intake' (page 8476, first column); 467

COnCLUSTON

The Association supporta_the_Panel's classification of phenylpropan3lamine hydrochloride as_generaily recognized as safe and effective-when used in OTC weight control products. The extensive daLa discussed above demonstrate the safety of phenylpropanolamine at the I50 mg daily dosage_level_and amply pupport the safety of the currently- marketed weight control products at the 75mg daily dosage level. The Association also supports the Panel's recomnendation that the combination _of__ phenylpropanolamine and caffeine is_safe and effective if labeled as an anorectIcistimulant;

The Association believes that weiiht control active ingredients in cymbination with vitamin and mineral supplements should be allowed, contrary to the Panel's recommendation. in addition the Ao-ociation ur3es that FDA reject some of the Panel's recomendations with regard to Category It labeling.

The Association appreciates thl_oppnrtunity to submit these comments and hopes that the agency finds theM helpful;

Sincerely,

THE PRO ASSOCIATION

James 'p, Cope President

a1 .7O 468

EXHIBIT 1

'Comparison of_ the_ Anorectic Activity of Prolamine and Pladebe WithoutConcomitant_ Nutritionally Balanced_Piet.' Marianne Sebokv M.D.,_Staff_Physitian, JFK Memorial Hospital, Philadelphia,PA; A double-blind siz Week Clinical-evaluation wasconducted with 72 patients who received either 35mg_phenyIpropanolamine and 140 mg_caffeine (sustained release) or apIacebo_twice a day; Throughout_the_study,_ no clinically significant Variations at sitting blood pressure_or_pulse_were observed or reported. PPA patients lost statistically significant amounts of weight compared withplacebo patients. °Double-Blind _Evaluation of PhenyIpropanoIamine-!Caffeine Product as an Adjunct in the TreatMent of Obesity;,_ E;_R;_dollyi_M,D.2_BioMetrics Laboratory, Clifton, NJ; Pindingsi_A double -blind 12-week study_of 63_patients revealed_that 21 patients on_ _ phenyIpropanoIamine-caffeine showed an_average weightloss of 15 pounds, and 13 patients on_placebo_showed aweight loss of 8 pounds over the -12 -week testperiod,- or pounds per week for the phenylproppnoIaminepatients _ compared to ;66 pounds per week for theplacebo patients; Side effects were minimal and- equallydivided amoung placebo and active drUg groups.; One patient- on- the active medication_reported hypetatIMUlation and sleeplessnessand one patient on the placebo noted extremenervousness; No Significant changes in blood pressure or pulseraLe were observed. 'Double -Blind Clinical Evaluation of the Anoredtid AttiVity of Phenylpropanolamine_Alone_Compared to_Phenylpropanolamine Platt Caffeine in the Treatmentof Outpatients with Exogenous obetity.'Anthony Contei_M;D., PittsbUigh, PA; _In an_87week douhle-blindranaomized clinival test, phenylpropanoIamine_50 mg wascompared to- phenylpropanolaMine 50 mg with caffeine200_mg isustained reIease;) _Of the sixty-two obese adults whoentered_the clinical evaluation, both_groups lostsimilar amounts of weight; NO deviations frosibaseline_werereported in sitting blood pressure (systolic/diastolic) or pulse. 469

In_an open, crossover comparative study, the bioavailability of 25 mg phenylpropanolamine (q4h, IR), 75 mg (od, IR) and 75 mg (od, SA) was tested in 18 volunteers by Donald Flasteri_M;_D. No significant blood pressure effects were reported;

Griboff,_et al., reporting in_Current_Therameutic Research 17: 535-477 TT75, found no significant changes in blood_pressuce or pulse_ measurements in a double-blind parallel study on 66 volunteers recei7ing 25 mg PPA with ;90 mg oaffeine (tid) or placebo. PPh patients_lost significant amounts of weight compareC Kith placebo patients.

Altschuler, Sebok and Conte conducted 6-8 week, double-blind, parallel studies using 50 mg PPA (0d; SR); 37.5 mg PPA ;bid, SR), and 25 mg ePA (tid, IR), respeCtively. No significant effects nn blood pressure._ or puls rate were reported or observed. Significant weight loss was reported;

In a double crossover study_conducted by Bartley G. Hoebel, Ph.D., et al., at Princeton University, Princetoni_NJ, pbenylpropanolamine (25 mg, tid) reduced body weight in 70 adults significantly more thana placebo pill. During the first two weeks both the subjects takinj the placebo and those taking phenylp::opanolamine lost weight, but during the_second_two weeks only those takin4 the_ drug_ continued to lose. On daily questionnaires those taking the drug reported no rhange in the way they feltor the time it tcok to fall asleep;

F. B. Bohen Ay, M.D., Brooklyn, :.tew York, conducted a single-blind, four-week, crossover evaluation_of 60_patients ili_Dr._Bohensky's_private offices; Appedrine (25 mg phenylpropanc-Aamine plus 100 mg caffeine plus multivitamins, tid1 was colvared to dextro-amphetamine and placebo as an_ appetitie suppressant. The results indicated that the pheny/propanOlamin:- groun (Appedrine) on the averase lot 1.98 pnunds per week, the dextro-amphetamine group on the avervis lost 2.3 pounds per week, and the placebo gmc.? en the average_ lost ;62 pounds per week. No significant changes in blood pressure or mood changes were reporter? observed. 470

Exhibit 2

a Massachusetts College of Pharrucy "1'7 and Allied Health Sciences

September 25;1981

.. Richard Crout, MD, Director IStrreau of Drugs, WD-1 Food & Drug Administration 5600 Flihn.T Lane Rockyille, MD 20857

Deer Dr. C.roUts

This letter is in follow-up to our discussion. on sustained action dosage forms and your interest In the-Physiological response to a 75 mg bolus dose of phenylpropanalamine_HZ:l. You will atral4 1rm sure, our meeting on SepterriberilthIn the Commissioner% office at which time we reviewed_the F.R. publication status of the Advisory Reflew Panel on DTC Miscellaneous Internal Drug Products Proposed vlonotxaph -for DTC weight control drug products. As on avid student of the. sustained action dosage_ form_ and phenylpropenolarninei 1 was certain, r . . t s I advised you a_t_ the meeting, that my_ tiles Included descriptions of everlmental work where _a 75 mg bolus of PPA had been administered to human volunteers Inplain ImmediRte release dosage form and the hemodyn_amic reiponse studied. The SBA for NDA 18-0990 "Contac" provides Information describing three watt cross-over study employing twelve normal human volunteers. The three dosage regimens were: (A)Two '1"..**r..._r" sustained action capsules containing 75 mg PPA and 8 mg (PM per capsule.

(B) 75, mg PPA aritq 8 mg CPtic plain thvg as a bolt: ,

The bloavellabllity study deter_rnined plasma levels 2, 5, 6, 8, 10, 12 sod 24 hour periods following_ dtu_g Ingestion.In addition, blood pre.- -^ and pulse (supine and standing) were taken

1"/9 L on gwood Avenue Boston, Massachusetts 02115 Phon. (617)'132 -2800

Reprodu-ed by The Proprletary ,eissociation 7/16/8 471

st_1,_ 5_ and_11_ hams _after dr.4_ eostng.No clinically significant change In blood_ menisci" pulsa_in .any_ volunteer during the study was reported. might add this Information_Is especially Important in view of the report by Horowitz, et aL_Hypertanslve Responses inducedbyPheny*ropanolemineInAnorectic_ and 6econgest.1.-4 Preparations", Lancet, 19801 116041. The Horowitz study would suiezest one misfit expect an increase In lupine d.astolle blood pressures in eome-volunteare ingesting 75 nPPA beut inasmuch as this den of PPA In the katrallan xtudy was reported to be_115_mg,_only 10 mg greater.However, no clinically significant siminges_ki blood_prissursers _reported in the carefully controlled study submitted in support of NOA 18499; At the time of our own stuthisi_ stack of Side Effieti frOM Orally Administered Phen_ylpropanolarnine end PleilY1PreOlinoleiane With Caffeine: A Controlled Three -Phase Study!,_Current TharneutiC Research 2.8., 135 -194; 1980) we received s small number ofthe tun-grid-4in product "Trimolats" for valuation. "Trimolete vtai the 85 mg PPA product reported on In taw Horowitz_paper. Thecaps des contained a _fine yollew powder lebellad to contain D-hanylpro- periolemine_ 85_ .mg pim ferrous gluconete, alcisnrpantothenetei thinning, riboflavin, ,o_yridoxine and-nic-otinamide. Only three capsules were received assaying_ out ar82.2 mg, 79.7 rrig and 83.5 mg respectively (tharege 81.8 wed).The PPA in these capsules was Immediately soluble In writer, and not in a sustained release form. Regarding _the integrity of the aisUlned release &sage form marketail_ktthis_e_t.:._ntry._1 would_ illts ti5 add -that our is1"oratories have, for years nowi_eveluate9 hundreds of palletized atTstained MINIM PPA dosage forma marketed by the ihotni3son_hrisdice Company. Ckir -laboretorics provide a nriodic quelity_tontrol _audit and_enmities ,function for Thompson as ...further ..cladc_Ao_Inre_u complienes of manufactured dosage forms with product specifications. Lem pissed to _Indicate we hive never encountered s product where 'taxe- - dumping"_ andar_ ei vitro Lusting occurred and the sustained release charteter of_s_dcsabe_!ormwas compromised. The number of sooty -and Quality control stepelekani_pricr batch release,_ ammo safety and efficacy of the sustained emotion product_ and provides an xceptional deems of coality_esmuranee _ruling eut any possibilityOf cceterence of "doss-dunning," .-C.linle41 bioavaliebility studies -have provided assurance of the effectiveness of the_ tImed.releste activity with excellent correlation betweensingle drew tg_ths.limed. release formulation (75 mg) and threr, doses of the immediate Wet -&sage form (25 m;) 140,15) at 4 hots !marvels. Hen-w,_ongoinsi_le yr quality control. In our oxperience, assures product perferranes level consistent With the in vivo results. 472

Thompson's 75 mg PP/ dormogo 4orrns art_rnartu- red to conform wit' vics u ssolution pattern A. - .

Fttlearle rn&L-Reieasr

30 = b t 22 5 = 3175 4 Sri = 75 37 556.25 8 BO = 100 The dissolUtion. pattern Is developed t;y turn; Irc at 2i 14 '6 and 8 AOUrS. . : T

1 trust these comments ai. a helpful sequel to our earlier disc:.ssion and provide some resistance tc yr,tu.

Sincerity, PFEIFFUt PHARMACEUTICAL SCIENCES LABORATORIES

1._Speirman, D.Sc. Professor and Executive Director

cc:Mrs. Barbara Bayer Marlon 3. Finkel, MD William E=_Dlibertson, Pharrn.D. mt Mark Novitch MD ".. Dr. Edward Steinberg

4j 1,, 11111111 111 .3*1-1 ,p1,4111,111 4 Eilliilline14144VI 11-i ItIOi.14 11111 el 11 hill111 1E ,LI'NI-A Iiir. jail I frig' fp 13II rilid 1 ei 12, 11$14.. 1,1 iv: illr If 11, 411 1 alltI 4111111 -1:11:113 9H fil lilt ;111 Ig 1. 4114I 1141 U141111 i$11 Oa 11111111111111:1411,171h 6'41' u.s.4 11111111'1111( LI ill ' 474

Ekblbit 4

THOMPSON MEDICAL COMPANY, :NC. 919 THIRD AVENUE NEW YORK. N.Y. 10022 1212) 088-4420

PROGRESS REPORT ON THE PILOT STUDY HCi "DOUBLE -BLIND SAFETY AMEFFICACY EVALUATION PRENYLPROFANOLANINE

IN EXOGENOUS OBESE PATI'..4TS WITH Ca:VERDI:EDHYPERTENSION"

katt=:

Hat - Ts- 1u'ss- , H. IL

; 33134

Subafered re:

Thompson Medical Company, Inc. July 16, 1982

Prepared by: fiarraper 475

C )NTENTS

I. STUDY PURPOSE

II. PATIENT POPULATION

III. PATIENT EXCLUSION CRITERIA

IV. STUDY DESIGN

V. STATISTICAL METHODS

VI: STUDY RESULTS

A. Patient Population. Profile

B. Vital Signs Data (Stfety and Analysis)

I. Blood Pressure and Pulse Data

a. Baseline vs Biweekly Treatment Values b. Haseine vs Biweekly 15, 1. 2, and 4 Bow: Values c. Intraweekly Treatment Value Comparison,

2. Laboratory Blood Analysis Data

Treatme:t Value Comparisons b. L.',ekay Laboratory Values

3. Laboratory Oral Temperature Data

C. Weiiia. Loss Data (Efficacy Analysis)

D. Side Effects

VII. CONCLUSIONS 476

S1GDY Mr, 4K

The purpose of this study is to evaluate the efficacy, tolerance, and safety of phenylpropanolamine Hdl (PPA) vs placebo in the treatment of exogenous obesity in patients with controlled, stable hypertensive diseases.

II. PATIENT POPULATION PROFILE

The patient population profile included twelve (12) patients_ in the age range of 25 to 67 years with exogenous obesity and controlled, stable hypertensive disea

A cev.:rolled_,_ stable hypertensive disease was defined as diastolic blood pressure at or below 94mmHg. The hypertensive disease state was controlled with thiazide, with and without concomitant potassium supplements.

Exogenous obesity was defined as at least 101, but not more than 552 overweight as calculated using the revised Metropolitant Life Insurance Company Statistical Book 47:1, 1966.

III. PATIENT EXCLUSION CRITERIA

I. Patients currently using concomitant medication which would interfere with the evaluation of safety and /or efficacy, i.e. MAO inhibitors.

7. Patients who have suffered a recent (3-6 months) myocardial infarction or with severe cardiac decompensation.

3. Patients who have had recent (3-6 months) surgery.

4. Patients with elevated venous blood pressure.

S. Patients with unstable or accelerated anginal episodes.

h. PntiLats who exhibit complications of hypertenstion or .trioxelerotic cardlovascular disease, such as cerebral fachemia or v., a

7, Patients who cnsnot adhere to the protocol vistc 561

S. Patients who are pregnant or Inc'oring.

9. PaC.nr 1 who have been on weight reduction programs citation during toe three weeks prior to this study's !nisi..

IV. ST:Tv RESIGN

1h studs was a single-MIA crossover study which r....,ded for six weeks aocordlng to tht tollo,log medication and dosage .l

WEL,: I "h,nvlor.nanolamine 15 me. caffeine I00 m r I.A. (one hour before meals) 'e1iF. 2 477

IV, STUDY DESIGN / loed) WEEK 3 P7accb), 6.1.d. (10 a.m. & 4 p.m.) twashout period WEEK 4 WEEK 5 Phetvilpropinolamine 75 mg. o.d. (10 a.m.) WEEK h

Data was colle.ted according to the following 'schedule:

INITIAL ';ISIT (Day 0) Chest X-Rey; Background 4 Clinital Data

`T.EKLY VISITS Body Weight, Vital Sign (oral tempera ture,h1o,d pressure. pul.), Appetite Suppression (degree, duration), Side Effects

MEEKLY VISITS Physical Examination, Supine Electro- cardiograph_ Tracing4BloOd Treesure and Pulse 4,1,2 4 4 hours after initinl dose. V. STATISTICAL. HUNTS

Analyst of variance (t-testa) was performed on the dif:c.rence between baseline vetoes and (a) biweekly treatment group value-. and (b) blwoekly treatment erouo values taken at M. 1. 2. nod 4 hours f rhloodore/inure and pole. measurements.

Theme variablen were also tented for scan[ for esma treat- mentk"tnip_dor inv. each treatment v- week) v 4. week 5 v 6).

Laboratory vela... (glucose, trial), :holentetol, GGT7', SCOT. LD11. 00.1 luta. pot W.'S hilt,1.1110rLla and Dm ruren) were compared for 'tent- ( It. tautdi( f erenceabcrween base line .and tel ot _treatmentVIMp we torte. . Altt,t,Jabot ory values for placebo vmedicated treatments were omperml.

frellirs (appetite suppreeston) and wwight loon meneulements were e adltiortitot difference, betweenhaaelinc and rod of Cren[ment group value.. A ti): onfitvn,c level van ;lard totent the et at is Icaln lent f :caner of Ile data.

VI. 'al -D1 NI !,7'I

A. PAI I r::rrofilAllob

Teoofthe Intl I..1nil ve.patloll( 0111i let .41the sto.ty tat i 14 AI it II).1fIr:r1 thef lent era...wet it,loutvet d 1.1* ''IP I 0 1 . 1 V Inns holing .1 M4., told h i t Inrod ore, ;Iwo tnve, 1 ,,' v t , "'either rat lentt . 1 , I v et .eI es, t 1.o s.

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478

TAALE St: PATIENT Part-L-1431; F80w112

PA-711INT4 -IXTMED PATTER'S -0011,12114

tir'eSEA 12 10

SEA - !We_ 1 2 9

ALI (VAS) Moos _SS.5 _9A.S Lamps 25-67 25-67

SoDY_FIWIE Small 0 0 Nedluo 7 7 Largo 1 3

Iteaa 26.62 23.82 Vie. 12 -s. 12-54

INITIAL HEIGHT Memo 1116.7 1711.8 Rood. 1411-28,4 141-284

IDEAL STIGNT Mose --131,1 -137.2 lamp 125 -164 125444

8. VITAL SIGNS DATA

Pressure sod Pulse Data

a. t...1 is -vs -Illeree&ly -Treats...itValues !ANIL 2 lists the woe and ranee 'sloes !or sLood pressure sad pulse value* st Oseellee anat eod of ease trostmest ported. Figure I dlelly twos values graph:A(.11p.

Ms etAttsticAll, sloultvoutt_dltfosseces were_oved 8eposeo Use - Ilse values *Ad sod ettrsalitinnt valesfor Gaoled measure or eileit oesoursoonts. 479

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61-LA 4 *tft f!:_47 (721.2,t;__Itt,1 LAa Pulbe ..t.* I *15.-41 (St. DT 471.t.) tow-*6 (34.2)

At.A.,.4 Is, :1 . .1 70-4K4i12.2) - _ - ; 7.1 z. -4t'461.+) 4.0-.00 481.2) (79.45 S*Atr:1: i11l1..: (13C-ty10G-i On :1 C1.-I*S_(1.7.134 1-M-1-54'1124.2) 1,.14114 Il-17::(131.3) (WA) 111-1A (.4) 9G-ISO(1211.6)

Foos I YEAR BLOOD PRESUPRIlomelft MCIPCILS, RATE twooluse11004.1.11ES AT BASELINE MC END OF TREATIALAIT WEEKS.

*1441 e. os 480

1.1 r_7. ,11Pta Rate Mica fr...atturaed)

iNek.t.-c-,ct cr. c tc*.1.1 1 ltite tt.r naana acot_tlut_raa4. at Wt..* t:ctt:an14 peramair. at Lia.2 tar ate at 1 1. chat snot0. fir.: tor all Owe.- *1.-kures ; tiv scan at U... valises it._1110/111. In( , dift.resices were 4104 1; 4.11401.143. 71' afh: pule val Wt. I.alt time tires sad u.attcpa .iaaaga._a)clriagtk_ed 47.1/.statistically yrye -seen.Cltaicia 1.8701.firsnv, i easily ....int% 1J10) tfr at citar...a toet.irn bes..1 I./ We I 111.16 via Imes tor 7.311101,21.1tVf u.1 es, bet...WE :"Lsas r teat s bloat _prcra*.cra; Ws-ft yang; Pistol Ic blaad ^talcauta. tn.**. 7G-9C. NOIR) and ireataffat 1

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pr..fCTS 6o Pvt";eot 1,7) rporteal (*aline *1.404.4 aaa disalea durtst tA 11yee verb of teed t . at lOtfSeePPA.t . .1. ;46..1 et,to:ea_torreon Gasoline and S.,I, add . trols.a.: and pull.. wal-oes pe:vtles safety data fvr tr.* wirrrs- tvp.r pat 14Zr p,S,..141t1.4:311.._is log4ifferit9,ell_Itort.ett 1.4.,1.. add om.oll ZroAfreent "aloe. .L5....vd aos-staall:-at dlffarea.e f:: O: 4 .11144211., 641 IX tric..caly treatment cooper lava* atormit 11W+ .hal- t: .ot :tittererrt.. 74.t. ess.-lts 1..otLitv tte cdatlrmattons of ttlo pilot Study. f ettivempon of OtArcvlptotoe:Lo.ne 447pet:te in,PET044." 146 for atalle, anti-tams:ye popk.latm.na wa as 0.1AtontLatad la tats pilot o t.dv-roe pallet's:a reciIn :Sad and 75 as (o1) i_oMeo vLat: loss of 1-9 po...nds end I.. pommds per wet,, utiLib gra.eAs the r.,4 flodlo ofGran oot4tz loao of LC itovold par voso foe 1::.00C pat:eons rtotrts rterecripttant me/0'a loss alas, -a astrasatod La tte lievta, of Amt-ctoolne-Gike Dross t. tt Eldr ix Crbv.1,. to Perototttt fi,111,P.:t ?I.Grar,rA. 4.*1-1.10.,:.6.. Ir._ Government ..lots /Acorn of reduce. InunLer le.11wg (it:) ran ttea;or ma _g (.at lent, tIvt

;!, Itifftg t t trot. 487

THE PROPRIETAIW AS503ATION

' 31C 230ix..1.cor ,3C

o,sgurt 27. 1931

Arthur Rell_Rayesi_Jr.i M.D. Coomissioner ef rood_and_DrOgs Dockets_maaapesent Sranch (SPA-35i COOM 4-42_ Fool ami Dr.il_isistration 5400 filbert Laws Rockville, Maryland 20157

Reply Comments: Weight-Control Drug Products _ for Over-the-Counter demon timer Ebtablishment of anon)lroh: klvancs Notice of Propoitel

Fie Are. f- 022

Dear Sir: Comments were due on_3uly_21i 1912._ on the above proposal, whict consists of a_Peport and_Proposed_Mosographoc_thir_ Advisory tans! On OTC Miscellsosoes_Internal Drug ProlaCti.____ cough id by the Food and Drag_ Administration usider_lte OTC Anal Revise. Reply Commit, vets to be s2baittod by August 27. 1912 These evilly conmants are tiled on behalf of Tho_Propriotary Association, a 101-year-old-trade_esSOCiatiom. tne_active members_st vitich are engaged in the maIufaCtere and distribution of nonprescription or over-the-counter medicinal products, Members of the Association-are eub:ect_to the Pinder.' ?MA, Drug and Cosmetic Act (21 U $ C 101, et ileg;) 4*d stf4 intir4a43 in and affected by this Proposal: TheSe_replY_cOnnenls are not iAtondol to supersede any %Mich soy be filed by individual members of the Association.

COOWtAti Which Assert thet_PhemylOrOPtinOlawifte Causes Nigh 210)d PrelCira or (Aber Adversg IteaCtionti

The prinCipel_COncern, of the_Center_for_acience in the Pea/14 :444:.44 (CSSIP regerding tbe Witty of

,4 &o 488

phsnylpropanolanine rest on what CSPI describes -as -'the known- tendency of WA to raise blddl pressure...." (CSPI. p. 5.)TO the contrary, there haie been no studies submitted or cited by any participant in this proceeding that support the proposition that VPA has a 'known tendency' to raise blood pressure at the dosage levels recommended in the SAM

Ln it.' discussion of the relationship between PPA and hYPertension;,_ csis7 states that after the Panel's report (.41 weight control prodocts_containIng_PPA_was_eubmitted_to_PDA_In 2979- 'several reports of_alarming cardiovascular reactions to reconaended_quantIties of-PPA- appeared 1n_thi_tW7 medical literature.' (CSPI, p; 'In_respotee to this evidenc4,' CSP: goes on -to stateh_srDA took regulatory action to remove from_the asrket 311 weight control produCts-containing singls, immediate-release :loess of grouter thin 37.5 mq of PPA and timeireleast doses of greater than 75 mg.' (CSPI, p. 5.)This is incorrect. In actualit7 the action by CDS to limit products to single, immediste-reterse doses of aot greater than 37.5 al of PPA and timed-relecse doses of not greater than 74 mg was based on the agences poeition that products which contained hilber doses were not marketed OTC prior to December 5h 1975h and were, therefore, 'new drugs.' (47 Fel. 112. 2469, Fehr:my 26. 1992.)

CSPI cites the_dooble,blind_trial reported ny_liorowits, et_el., in_19210_as substantiation for_its_essertion_that_the alai/able eviienze_does not supports Category_I_classification for any dose of PPA;_ The Assaciation_coamented_extenSively_On the __ Morowitz study (1104 p; 5 -of PA- Comments); -end now Idabel to ail that the study by C. 4; Mitchellh-referrol to-on page-7 of our comments, did not report coapsratle results with the SO a/ timed-release portion of the study. In cross-over study, ale normotensive volunteers received placebo or SO as PPA plus 0.25 mg bellatonna alkaloids. Mood pressure and pulse were recorded every 15 minutes for the first 90 minutes and every 31 minutes for the next 90 salutes after dosimg. Mitchell xrport40 no statistically significant differences between drug and placebo on mean arterial pressure or pulse.

Mor_did 11 percent of_those_persona_vho received 50 mg of TPA in_a_timedl-release _fore Morowits_study_levelop 'significanti_somitimes severe- diastolic hypertension,' as CSPI asserts; ACSPIh_p; 6,) noroeita reported that four of rho 37 subjects had a diastolic rea1ing of 100 or sore, and reported that one of tbrats_fOUr participants -had e maximum supine blood pressure of 145/110 ea 0g. Presumably the subject with the 145/110 mm hg. reading hail the highest diastolic reading of he four subjects with readinjs of 10D or more. This Is not equivalent, however, to reporting that the subjects had 'sever', 489

diastolic hypertension." as Mr states, nor did Horowitz so classify those subjeCta. Moreover, although Horowitz stated that three_subjects in the 95 mg portion of the study received anti-hypertension therhPY. be did not report that any of the

oubjects in the SO mg_POrtion of the study received - anti-hyperteaSion therapy;

CSPI further asserts that one would expect the elevated diastolic blood presSzre readings reported in the subjects in the Horowitz study who received a 50 mg timed-release capsule to occur in more people if a 75 vg dose were ingested. (CSPI, p. 7.) In fact, the Noble study cited on page T of our comments demonstrates that no such result occurred. The speculations of CSPI are further ne;ated_by the fact that in 1981 Approximately five billion dosesof -PPA were taken in the form of cough/cold end weight control OTC products, with only a handful of reports of adverse reactions, which appear to be either idiosyncratic or due to overdoses. The consents of the California Association of Neurologiosl Surgeons, /nc. and those og Arthur P. Shins, Pharm. Def Beecham Laboratories, taise a similar safety concern when PPA is ingested. However, the reports cited in those comments simply do not indicate that there is a relationBhip between PPA and the reactions reported when PPA is ingested at_the dose levels recommended in the ANPN. The comments of the California Association of Neurological Surgeons, for example, report three casts of adverse reactions after ingestion Of PPA.Caile 1 and Case 2 are, respectivellf, a report of an overdose of an OTC weight-control products-and a report of ingestion of an illegal 'Iook-altke' product. Case 3 is a report of an elvers. reaction after the ing estion of an OTC 'diet pill,' which is" not otherwise telentified. as to Case 3, it should also be noted thst the report states that vomiting occurred immediately after ingestion and that the adverse reaction occurred after the vomiting. It is unlikely, therefore,_that the_adverse reaction resulted frog the ingestion of the 'diet pill.'

Similarly, the reporte_Cited by Shinn involved overdoses, ideosyncratic reactions and/Or illegal combinations. Casa -1 involved -a patient with -a history of epilepsy who bud a seizure apparently coincidentaIly_wit h the ingestion of two combination cough/cold producte. 1h Case 2 the patient had consumed three to five ounces of whiSkeY just prior to ingesting two 'black capsules,' each containing a combinatiOn of 200 mg caffeine, 25 mg ephedrine and 50 m9 PPA_. a combination which VOA has since declared to be an unapProvel °now dfug.° (47 Fed. Bei. 35344, August 13_, 1982.1 CaSe 3 again invoived two "Erick capsules' containing the same illegal combination. 490

CSPI asserts that the_recommendel_label warning is inconspicuous and inadequate to protect_ persons who have hypertention, heart disease,_diabetes_or thyroid disease from ingesting weight control products contelning_PPA; (CSPIi pp. 12 -13.) As an examination of the labia_varnin2s on these products shows, the warning is clear_and_conspicuous, as, indeed, Section 502(c) of the Act and FDA's regulations require it to be. CSPl_further asserts that iclonsumers have an understandable tendency to_believe_thet drugs available on an OTC basis are safe for_most_potential_purchases, (CSPI, pp. 12-13.) We believe that_this_is_true_and that it is also fully consistent with the philosophy of making_melication available to the consumer on an over-the-counter_basix.__In_stating that consumers do not read_IabeIs because they_believe that OTC medicines are unqualifiedly safe for everyonei_ CSPI is not really questioning the safety of PPA as_an OTC: it is_really questioning the fundamental principle of -self- medication itself -- that people are capable of using .0 OTC- safelyand effectively if they 'follow labeling directions.

Comments Which Assert that Phenylpropanolamine is Unsafe Because of Alleged-CNS-Effects

CSPI states that PPA_Is_unsafe for use in weight control products because of reports of_adverse CNS effects resulting from-the ingestion of PPA. _CSPI_concedes that "Inlone of these incidents proves definitively that_PPA_can_cause mental derangement,' but contends that the structural- similarity -is there... between -PPA -and the amphat-omines, adrenaline, and related sympathomimetic amines. (CSPI, p.3.) CSPI couples_the structural similarity with case reports in the__United_States and other countries linking PPA With adverse CNS effects._ CSPI cites several reports, including the Dietz survey listed in the preamble to the ANPR as Reference 9, as support for the proposition that there have been 'scattered accounts that-even normal doses of PPA may sometimes cause or aggravate psychotic episodesi_hallucinatlonsA or other severe behavioral- aberrations_that_mimic amphetamine reactions.' (CSPI, p.3.) we submit that the_Dietz_survey does not support the propozition_that_there_are_adverse CNS effects associated with the use -of PPA at the dosage_levels of the products currently marketed or the dosage IeveIx_proposed by the Panel. As CSPI points out, the-Diet2_survey is_composed_of_scattered accounts. (CSPI, p. 3.) -In- addition, the_seven_cases_referred to in the Dietz survey, which were taken from record cards of 491 patients in emergency rooms, are_accounts_of Isolated cases of Individual adverse reactions; There_was_no possibility of verification of the actual doses Of PPA taken since the PPA was not taken undler controlled conditions, and there was nn follow -up to determine whether the symptoms reported were repeated under the same or different circumstances. The -other reports cited by CSPI (CSPI, p.3, fn. 9) also fail to support_the proposition for which CSPI cites them. With regard to_the_Achor and Extein_report_of_precipitation of bipolar affective disorder in_three_patients who had been taking diet-aid products containing SPA,_one patient_had_been taking twice the recommended dose; and the dosage for_the ocher two___ patients was not reported. -Therefore, one of the cases clearl/ involved an overdose, and the remaining two cases may have_as_ well Furthermore, according to.the report,-all three-patients had histories of mood disorders. Finally, the report did not describe the patients' psychiatric status immediately prior to tekiml the diet aids, or after they were withdrawn. It ii therefore_impossible to evaluate whether SPA played any role in the psychiatric episodes reported. Tht_Schaffer_and Paull- report cited by_CSPI involved one patient wha ingested three -to five_piIls esmh day from two separate bottles of diet pills;Obvio4SlY, tbm_reaction of that patient is of no use in any evalmatte5i of PPA. The report by Norvenius, et a:., cited by CSPI. Matta with complaints to the Swedish Adverse Drw9 R tiow COmmittee. It is unclear from tbo report whether the total nienber of complaints was 61 or 65. In any event, five patients were reported to_have_hal psychotic episodes. Put the report does not give dose levels for any of the patientS. Since 45 of the patients were under age 16, it is preibable that.many of these patients ingested acctdeatai_overloses. Moreover, the report specifically- notes -that one i7- year -old male_had_taken °large quantities of a PPA and brompheniramine combination product. In view of the absence of data on -the- precise dosage ingested in each csse, the report essentially has no probative value. The Wharton report relied upon by-CSPI describe* a psychotic_ episode in a patient taking a cold medication containing 12.5 mg mf PPA. Phenyltoxolamine, phenacetia and thonsylamine. ne exhibited paranoid psychosis after an eightday period in which be_had_ingestod 30 tablets. No was treated for the paranoid psychosisi_but_eight weeks after recovery he suffered a similar reaction, elthough_in was not_tating_the cold melication at the time. Therefore; the_pxychotic_reaction apparently did not result from the ingestion of SPA.

194 492

.nallyt Can cites the Kane and Greene report of three Atlantis who took nasal decongestanta containing PPA.The reaction of two of the three patients simply does not support the_CentsC!s_position.__Cone_of the patients had previously been treated_for_undifferenttated_schicophrenia.That patient's reaction may well have resulted_not_from the_ingestion of PPA but-from apteexisting_mentaLcondition_.___Another pattent_bad_ used two_bottless of the decongestant witbin_ons week._ There is na- indication -as to the actual amount of PM taken at any one time. Accordingly, once again, the report cannot be cited as support for any proposition concerning PFA. To summarise. the five published reports discussed abeve include 13 patients who experienced Psychotic episode,.Three of the patients IMO Chilalt08 111 years old ot ynuoger. oho probably ingested aocidents1 overdoses. and one patient was -a 17,year -old_who_rtportedlY had Laken *large quantities of a PPA_sed_broophentranine comhinstioolproducti Ancog_kbe remainiag_nine_patients._one hal_tsitsa more thold_the reconende4 dosevanother_may_bera_tokes_mere_than_tbs_recomescded dose ithe_only information avaiIable_was_that_the_pettent_toot_!two bottles'', one apparently-took-two PPA-containing_prepatations. but dosage wxs_not_specifteds four-had historian of affective illness or-schiSophrenia and-one-of these took mere than the recommended doses and-one patient- experienced another psychotic episode eight weeks after he had discontirued use-of-products containing PPA. Moreover, it itietI4 be reiterated that substantially all be the complaints reported by-norvenius, re eosplaints of restlessness. irritability, eft. fit these reports primarily involved children IS rears old_and_younger anelo_thetefore0 most me the cases undoubtedly involved accidental ingestions or overioaes. CSPUaIso cites_anather_cass In which_allt7ed &loots, Cla reections_occurre4.__(CSpf p. 7.) The case involved -a 44.,year -old woman who- developed !confesion_tandl_grand sal approximately an hour -attar taking a 75 mg tilled-release weight control capsule; _As a careful resding_of thil report-of the incident iodinates. the woman- had previously experienced grand :al seizure reactioas to coegh/cold medications. Therefore, her grand ins Seizure reaction was tdiosyncratAc.Theta Is, moreover, no established_ csntraindieJtion for sympathonleetio drugsfor epilepsy.

Aelying_on,C.11-111=.' v. av 1.1.1.4 v. Federal-Trade-Comp isson. 30 FTC 77d , __h_ 114E Trade Cases _1 it 711: (7th W. 12791._CIFf_assects t t PISA is unsafe be-cause the advertising for- weight- Control -products containing ?PA which dots not Include a health warning la misleading. (=PI, p. 13).The 493

relevancy to_ this_ proceeding of the MI6 action inthat case is dubious at best. In any event, CSP/ misstates the scope of the ruling in PerteK i Diet-itch. The holding was limited to -the particular advertisements at issue in that case. It was not applicable to all PPA-containing weight control producte. Moreover, as PDA knows, the Panel recommenieda number of label warnings for these products, as discussed above. There is an absence of any evidence_establishing that_adverse CMS reactions are o side_effect_a_the_ingestion_of PPAit the dosage levels proposed_by_the Panel: In fac, the marketing experience of cough/cold and weight control products coataining PPA in the Onited_Statts is support for_the proposition that adverse_CNS_reactions are not -a side effect of tht ingestion of PtA.__Purthermorw,_the marketing experience is arapported by a recent_doubIe-btind, cross-over study by Seppall, reported in theAtiLL11121LIALRLSWIS11Ett01121221- The sePPele ste4y, which *leo laChide4iitiblitaaiies:taat providedan_ active control, tepotte4 an euphorie effect and en improvement in perception and reaction accuracy following ingestion_of_PPA_ it a 50 in dos, level. Seppaln stated in conclusion_that *Mt in noteworthy that mood elevation.,,was not_noted_after itreatsent with] phenylpropanolanine."Accordingly, in_vpow of the results of the Seppala study, the_aceumulated experience froa the testing and marketing_of_cough/coMand weightcontrol products which fails_to_indicate_that ingestion_of PPk in the doses proposed_by the Panel results to adverse CNA reactions, and the tact that the cited-reports -of adverse CNS reactions are_either_reports of ingestion of doles above the recoemended dosaut_level ovate- isolated incidents, we submit that no evidence_has been identified that indicates that ingestion of PPA it the_recommended doses is unsafe because of possible adverse_CuS reactions. We believe, therefore, that further clinical testing is unnecessary in order to evaluate the safety of TPA at the dosage levels under consideration.

CSPI.-citing a letter from the British tepertment_ofAsaithand Social Security, states that only one PPA weight control product is marketed in Britain and that the product_is prescription drug, and implies that the PDA should adopt similar policy with respect to weightcontrol products containing PPA. iCsPli_p. 13.1_It_should be noted that Sritain does permit the aarketing of_OTCAlruga_containing PPA. %entity and James markets Contac, its OTC cough -cold product containing PPA, in Britain.

27-436 0 - 84 - 32 494

Comments Which Assert that PPA Is UnsafeBecause it is A Drag ofkbrase----

CSPI and G. S. Stickler,N;D;;_cite drug abuse as_a reason for placing PPA on prescriptiOn. (SCPIi 1213.1.11_ Stickler, p.1.) for Poison Control Center CSPI relies on Natonal Clearinghouse that reports and Stickler,citing no sources; simply asserts PPA is the number one street-drug,at least_in_Minneapolis and OtObanIy in other cities in thiscounter." (Stickler. p. 2.)

The Association has several comments cs..the point, raise by CSPI and Dr. Stickler with respectto PPA and irJg abuse; (1) National Clearinghouse forPoison-Control Center* INCPCC/

made with (a) SxtrapdlitiOna of MCFCC_data_must be section since -the data are_derived_fromonly 10% of the nation's poisoncootrol_centere. and the 10% are not necessarily a validsample. ingestions or (b) The data reflect all reports_of other incidents, whether aeriOUs_ornot. - -Asst of the - reports discussed hi CSPIpith respect -o PPA were_made_by telephone, rarelyitvolved_hospital contact_and. on the average, retainedin mild. if Any. side effects. p.5). 'a Litt, percent of (c) AS CSPI concedesACSPIt the CIiatinghaase_PPA casesinvolved Children_ . The Association notes thatthis percentage is Dago indeed over 40. That is, over 40% Of the tile* involve children under__S yearsof age. Placing an itigtidfant_oo_prtscription to eliminate unsupervised ingestionsby children it not, the association submits. alegal or wise measure. As FDA knows, The ProprietaryAssociation -and its members have long been actin,in_working to _ reduce_unsupervised Ingestions ofmedicines by children._ The Association hieparticipate±_in governmentsponaored coaferaheas_and_veriaus mducational_activities on the Otibpicti_willieIts *sobers have_been evpetimentIngVithi testing. improving, and_uslWearious focal`of tfotelaI pettling sites ItS5,___ttelltssto say, the xttociotton supporta CSPI''; attempt to[edge* 495

accidental ingestIons,_including_ingestions by children. of_the products_subject to this _ Proposal. _Tha_Association_believes._however, that_attempting_to combat such ingestions_by _ placing a_drug on_prescription-on the-basis that it is 'not generally recognised as safe' for OTC use is not proper.

Section 201(p) of the PDC Act defines a 'new drug' as one which is 'not generally recognised ..as safe and effective under the killatkkkiLUPto,mended. or- suggested -in the latteling theuol,.._,' _(tmphssis Iddel.)_ In so defining tte_tern. Congress- recognised that -any drum_cars_oe unsafe-41 used_incorrectIy, such as_ taken Internally when it should be used topically and/or taken in exceaSive amounts. Congress therefore sought to address the question of WhethAr a drug is safe by considering the safety of the drug in connection with the adequacy of its labeling. incluling Ito dosage recommendations, sunned of administretion,_ warnings. and other precautions,__Therefore.__ unless the labeling of tbe products subject to the proposal prescribesi_recommends. or suggests ingestion of_amounts which_are_tosic._such_ products do not meet the statutory detinitinn of new drug.'

The Consumer PrOduct Safety Coemission (CPSC), on the-other band. her she express Congressional mandate 'to protect children from serious personal injury or serious illness resulting free handling. using, or ingesting' these and other products by requiring special packalls7 where appropriate. (140 U.S.C._ 1472141(11) Accordiogly, the Assotiettoft_suggeste_that CSPI submit to_CSPC_what_information it has on accidental ingestions of such_proluets_by children._ ?Jai bowevtri_is_with*at autbortty to proceed against such products as "n*w drugs.' Not is placing these products on prescription necessarily useful swans of protecting children from' the dangers of unsupervised ingestion of drugs. Unsupervised ingestion by children is a function of the accessiblity of tbe drug to children and the adequacy of parental supervision, not of the legal status of the drug as prescription or OTC. 496

of_ (d) The Clearinghouse data include a number suicide gestures.TA* Association netts tha: dent of tho_gestures succeeded. Moreover, -the _ l'afaty of OTC's. which are productsintended to be titan accord-Awl to label directions, cannot properly b. judged on_the_basis ofdata regarding their use in attempted suicides. of the (e) !For a ventral but mort_dttalled_discssaion data contained In the AUgutt, Bulletin, the Association is enclosing as Attachment a written comments ofChstles_Winicki Ph.D. Dr. Winick is a Professor -it theCity University of Now fork Graduate SebOol, co-editor of_the_ d 4 u e. e contributing_eitor othe MTPMIIIn 'suss and Addictive_OtP,Wit and a ongt me consu tint to;- and-principal investigator on. manyprojtcts fCridtd by federal government agencies conctrnti with dtug r.bust;

(3) Poteutttl-Tor Abuse of PbOn4212PILMIBUlt) CSPI states that the- Griffith. et_4.i_study_which indientsd that PTA lacks nullpotentii: le_of questionable significance. -ho -basis for:this criticism 18 given. The Griffith Study_tas well-Contrialed and conclusively-establish*1 that-drug sea-administration proceduret with leboretcryanimas hale provIded_tn imlortant concoptual-an methodological focus for the pre-cliniCaIasiessmint of abusepotential. In this study, conducted at Johan Hopkins University. a quantitative ratiomeasure was d4vsloped which permitted comparison betweenthe reinforcing potency -of tither phenylsthylemine anorectics and_coctint_In laboratory baboons. The well-controlled study_clearly_delonstrats4 thatPP& r:Is a meta potential for abuse.d, Ssppala confirmed this in hunans,_finding_no_moodeltvatiog component from SO mg iiWildisttly avetlabltdoses.

'4) .20,11211tEELItikZaLLIK111

(a) CSPI_qutstions the saftty of P ?A for whst_tha__ Center atoms as the ingrediant's contribution to drug abuse from the *ale of 'amphetanime _ lookT!alitts. dsscribod by CUI as cedhlhatiens of PPA. vphedrine. and caffsine. (CSPI, p. S.) Tho Association notes that suchcombinations are 497

not- Category f_combinstions nor to anyone, to the Association's knowledge, proposing that they be placed in Category I.'hey are thus :sot relevant to diatom-113as of PPA when used accord:ng to-the terns set forth in the haPe. Indeed', FDA hen recently taken the position that such enibinations are unapproved !new drugs." (47 fed. En. 35344, August 13, 1982.)

(b) Ube, 18002_43_states_have considered and 13 1404 enacted Legislation_whic peohibisg trafficking In_whettSPI_describes as `amphetamine look.alikes.° Both the D.S. Drug Enforcement Adalaistration and the American Helical Association drive- developed molel bills alongthis tine. _fhl Association understands thatinstates which have-passed ouch legialAtioai the- problems of abuse of such 'look-alike.' hassubstantially declined. Zn additionb_b4th FDA and_the Post_ Offime Department have InstitutedLeisure actions gpildigt a number of sant/acts:4ns of such products.

(c) As_noted earlier, Dr; Stickler asserts that PPA Ill_the_nushor one et:nut-drugs-at least in ninneapolisi_and_plobahly in Other cities in this country;!_ tsticklor, V72.) It appears that what Dr; Stickler -is discussing is not !PA in the reconuOnded dose but rather PPA in the illegal co !nations discusved above.

COMients Which QUestios-tobt-EffwctIveness ofYlienTlyrooanoles104

On page 1 of its comment., CSPI states that oat Of It*concerns regarding welaht control_Products toataining PPA is thelack of ovidence to_espport elates of *Meaty.CSPI attributes this lask_of trishaw, to the drug manufacturers' allegedrefusal 'to reveal to the_scionitific community details of most et the studies purported to hack-claims of efficacy.*Seelless to say, aII studies submitted to FDA usder its OTC Drug Raviolion PPA are public.

CSPI tato lentils that the Panel's conclusion that_themew Studio* presented to it (Refs. through 11)- established-the Officacy of such products was .gnglitlild_lpy_tbs statementthat 'each of these studies is defective Inono or Nor. Important 'aye.' (CSPI, p. 13.) This statement is incorrect. ?tom Panel concluded that PVI. is effective and their findingwas 498

that: unanillous. What the Panel in tett &Mid wee While_each of those studies is defectivein 'A' a WI 1, 11-7,. ce the a1.1)111Y1 t anti be/ieves_that_the_combined evidence tf thee' itUdiee does establish theeffectiveness Of Ohieylpt.penolasine hydrechloride. (47 tsl. 047Si r4bfwarY 24. 1,82.)(0mphamis

CSPI states that the reeditsfrom the 10_doublk!blind studies_in the_poblic docket do_nOtsupPort_awY claim of efficacy.' (CSPI, p. If.) _To_the_contrarr. the_tollowing dath ropresenta-the achieved by patielts onphenylpropanolantn* an4 patients_on_placebo in eight clinic.' enultes ptnnontoil to the Panel: average Weight Lam 2.1 Week

Phenylpropanolsaine 1.14 lbs. INASS09 The difference is .40 lbs.

aoreover. several pears -ago PDa_ewaluatod210 double-blind studies in which prescription-appetite suppressant placebo.___These studies products were covered against data represente4101 new drug 4PPIlewtirowtAnd_fiaotsine4 Scheillei!._tf. reporting on On nsarly_10.000 patients. these tesuits._indicated that ofthe 4,541 patients_on_ active drug_and_3.100_patients onplaneb.._the_weight_loss averaged 0.14_pounds_per week morefor-each_pattent on result* With OTC anti** drug than_om placebo.__The _- products teetaining_PPA_compare favorablywith this_ by patients_on result: The average_weight loss_achleved the phenylpropm*lasine_programwas_.40 pounds mu than the weight loll Achieved bythe_patients on the important to point placebo-plas-diet program. *valuated in these oat that, when plienylprOpanoIsnine_was double-olind clinical Itudies_agalast_eitber lactose- capsule or an activeOta*Cription_medicationc_each patient aeliestIon. a 1250_calorie diet, was given. in addition to In other as well_as esPlicit directionstr64 a physician. wordsi_in_each case tbe placebd' -viiassociated with a diet designed to cause loss ofweight ander the_direction 6f-a physic's. Therefore, the anckintef_weight_loss _ achieved by_patients ontho_pbonylpropanolnelot_provain was even nore sigoificant becausethe 14% Was being-- coapared with another_active_progvas,that is, reduced klet nnd sedical directions as well asplacebo. 499

la conclusion, we submit that the cited studies are aufficiencl to support the efficrcy claim made by the varicus manufacturers, as thPanel concluded. CSPI cites the PTC decision in the porter 4 Dietsch case. discussed above, as if it were a finding on the ineffeCtivuness of ?PA _for weight loss, (CSPI, p. 14.) Again, this mitatates the case. The_gueetin pat at issue by- the complaint in Porter Diersct was °not whether the claims of weight loss are Tiris but instead whether it the time they were made (Porter Dietsch)- possessed reasonable substantiation for them.* !eau 6 Dietsch, Inc., 1974-1979 CCM ITC Complaints end Orders 1 21.320 at 21.329.The Commission made no finding as to the efficacy of PPA as an anorectic. Porter -e Dietsch. suers at 21,331.

CSPI also asserts that weight control products containinj_PPA are 01 no long_termbenefit_because_users_may regain Weight when use is discontinued._ OTC weight controlproducts containing PPA_ers sppetitefmuppressents which ere marketed as an_adjanct to assist_the motivated consumer on a diet. The Products_are earketedmith diets-that are based on reduction ire- caloric intake, and the labelling states that weight control will occur only if the product is taken while caloric intake is reduced, "fog do these products: claim ttbat weight will not be reoeined ff the person's caloric intake is increased.

Moreover, there is evidence which contralicte_CSPI's - assertion. Dr. Stanley_Shschteri_Prnfessor of Psychology at Colabis_Oniversiti, recently concluded a Iong-tere study to deteceine_whnther_overweight patients continue to maintain reduced_weiiht after_a_successful weight-loss program._I Asked about their weight histories, of 40 people who were obese at -the outset. 25 reported losing at least 10 percent of their weight (an average of 34.7 pounds) and therefore becoming no longer obese (that is, within 10 percent of the average weight for their-height and age), and remaining at that weight foran average of 11.2 years. CSPI also cites the statement in the American Medical Associatioh's AMA- Drug Evaluations thet_OTC_products containing PPA areonly minimally effective,* (CSPli_pp._14-15.) This characterisation-has Deen_repeated verbatim year -after Isar. but_investigation_of_ths_AnA's soorceereveals_that scientific_studies_or_proof of_any sort Are cited by tb4 AMA to support this description of PPA. 500

Comment. WhiCh Question theValidity_of the Siteereen Study Cl-ttd -bt-the AftitY end by TheProstistatx-AlsoCiatiOn

the_SilVerman_stady,,_ cited in the In its critique Of Agency's preamble and in- CSPI; -CSPIstates that the eaperiewmtal design is flawed_in se manyimportant ways that would he one could have predictidin edvaiice tbet no effects When analysed; this- criticiseamounts to seen.' MIMI, p.f.) tO0_110411 end thrte_pointst that the 'tidy groups were inciuded_only normal, healthy voldnteirstthat- blood pressure VaIues_were_presentei as means fot eacheutgroopi_tother than Individually, and that on'4 oneof the three_suhgroupe was Saving_consulted with Dr. SiIvermeni_te__ priflotpli_investigator for the cited study,the Asaectstion believed that these criticisms ofthe study ate entirely result *tit& witholit merit; The_si:ercalled 'flaws° were all the study detigh teplicitIy establishedin accordance With accepted dlinical proCeddrea to eliminateinvestigator or otivit bite; received active amlitotiati_ Tut, the pool of 37 emlunteers_whe With was div'led into threelialler_eubgroups_at separate sites a_ssperate group of qUilifitdinwestigatots* each conducting Of the other-two s4Ogrodpe.The total its -scaly indepundently was numberof_volunteers who roCeiVed_ective_amdication actually- the wane as the numberof voIunteers_who receiTrei active medication -tin- anoverdoes-of $5_41)_th_one of the Morowitz studios on which Cantell.* so heavily. In fen, CSPI characterises -that Sorowitsstudy as Ierge._teSPI. P. volunteers were nocmCli G.) SiMilarly, the fact that thm healthy ado'its was in- accordance withaccepted practice and was also true tf both of thenorowitz studies. The use Of veep Means to report_a1o94 Pressuresis an acceptable bioetatiaticaI procedure. three subgroups was ?twiny, thee faCt that only one_of_the each of the doubie-blinded _14 sled not_e_ffiew°in_ study. three_subgroups was treateddi2fereatiy_on_thil_score for souse order to obsolete reasons.Stcdy of one suhlttop was -open in the conditions in the actualover-thwecounter consumer tee of the product. The study of second group was_single-bitnied and the study of the third subgroupvas donbleblinded.._ The these cari%us fact -that all -three subgroupsetudied COnditiota puedaced no siggificantblood preesere_effects reinfOrces_the_conclusion that at thehested_dotage level, 25 mg, which is themost_comonlyTeacketed iieediett ream* _ dosagi leesI, Shenylpropenoleeineproduces no tdveree 'stool pressure efflOts;

50j 501

Ih conelusia, It should be noted that the Silverman study_is only one of some 60 controlled clinical_atudiesi_cited by the Association in its comments: which demonstrate that phenylptopasolamine_does_not ihduct hypertension; _This mass of positivri datai_tosether_with almost_SO years of safe use of PP* in this coiintrn cIesrly_outweighs_the_handful of adverse report's referred to in the CSPI and other comments.

rhe hrsOciation appreciates the opportunity to submit these seply commtAta.

Sincerely,

PAOPIIIETUI AStOCIATIOir

krone: President 502

TOOTHOTES

Sappala, 8,1_31- F.Kaeaunaya 12: 9- 4, 4 .

Griffithi et 11:1383. 1974; "Revlev_af_amphetamine-like cirul by J/ ScOetIle. th4 Podi And Drug kOministration.79t211LZAn i*elepective. POIIttv 7nternationel Centwr-Seritesbq PreventAvi Neditlite,_VOI; IIASreyi_GA.,-,ed.), U.S. Government Printih9 OCti0m, Washington. D.C.. 1974, ttls44), ToleY, 4/ "Don't Sell labit Breakers Short," Pavcholoiv August, 1942. Current TbermatisA222Algt, 21:I8S-194, 1910. N.Y., 1964. 4/ GoIdsttne6 A., lintatDWaL, MacMillan, 2r4; : . saitcatmratc oe1 potcog optaltOLOTNTZR tEPORT ONrawitzRopmlouimoz AmSuut 1981 Charles luta, ph.D.

. . .

I. She_ kligust, 1961 Bulletin of the National Clearinghouse for YODIOn Control Centers carried on article onphenylpropanolamine Weight Control Predatte.

for_the calendar_year_1079:_there Mere i_tetil_Of 144,262 reports .. , of all substaoCe0.__Of_thesei_739 vete diet -aide; Of Whiat 326 Mere named phenylpropanolesdoe products; or About% of IZ Of_the-totii. I obtained this breakdoo fro% severel_conversetiono whitb I hid with the senior author of the Poison Control Canter report;

2. As someone who has works.' for years in theeiidleiologY_of_embatence abuse, on behalf of the National Institute Of Drug_Abusi end other agencies. I believe tbas the -tone of the ?edam Control Center report

oo pherylprepanoleeine is -manly sod inappropriately peesimistic. I . do not believe that a valid extrapolation can be sods from the actual.

_date to the report's nett! of 10.000 phenylpropanolsmioe problem : Callao nationally. . , - .; _ ___ 3. She -cases reported to the Pollee-Control Center May or may not be '- representative_of what_ie_eCtnelly happening nationally. For exempla, ths_country'e largest Poltel_tontrol Center, 10 Nev York City, isone of the 90t_of_the_counIxes_Ceotert Oct reportine its experience to the national office TPA 10Z of the Centers reportiffig may not represent a valid sample of the national situation;

4. Of the 528 cases with product malmai_642_Invelved no syteptOes ofsay kind end the soloritY_of tbe remainder did not have significantaliptose; Overall, most cam were salsPhone-inforestIonal communIcetioes; _Only_: AZ_Involved a hospital contact. -On the Poison Control .Cestsr_scele_frem *Lief) to moderate( f)-to severe(3). ttm phanylpropenolmeintreports were, overall. mil4(1.4) - . . 5. Over two fume of the phanyIpropenolamlne-reports Imes under 5 years of age And almost ogle third_witoLet-mein14 and 11 years of ego. The former ere_presweed_to Weccidental-cod the Jeerer may have been seeking_s "high% if ao;_ther_wonId hi disappointed because pbenylpv.,- panolamine 10 net et_effettive stiOnlint;The smart of ittidietal- cases is another reflection of Ake importance of_the_perent"O rile ie management ef medication, is the hoes by always keeping meditetibna unavailable to children.

There were about 200 suicide gestures or attempts. Not only did note of these succeed but there wean* fatality im the entire year free

phenylpropenolseint. for any reason. . 5411

temporary breakout or peAing_betio 6. :The report does not - consider the first is employed by Urger _ by many epidinielegitti When s substance Detente of_unfamiliarity withthe-euhstintimal numbers Of lienfai. widely a barrage Of &idle publicity,,_wbena substance first bectoes : used,there is Often_ssherp_lsweasle cm--r..ncy room uttitei and calls, report, to poison Ventre' testers. IPstIVfor rrasg4KAMSS. After I yetr_Ot tun; the number ofsuch visits IAA- reports declines. It May veil bei_therefore, that the1,7, teports_cd phenylpropasolendme ,intidenta represent a temporary crestingwhidb %rill diminish is the 'near future. 11 . A substantial contributor to reportsof problese_with_phenylpropesolanIna 7; Oraneti *kith may include_phens1- is the- proliferation of "look-alike" propanolamine along With other drugs. I_understetwi_that in every sets which_has enforced restrictions *titbit'_'lock -alike " drogsi there et, been a uniform decline in reports -Of-problems vith_phtoylpropamolanine. Took-alikes7,,thls tan, is enebination If the state of Washington bine .with the cresting pbenemenon noted is thepreteding_peragraph, should pbenyIpropanolemine mentions to lead to a sharp decline in repots of Poison Control Centers.

Charles Winick, Ph.D.

CA:kJ

5n.2